Professional Documents
Culture Documents
Contents
1. Introduction 100
2. PIDs 101
3. PIDs of T Cell Function 103
3.1 Defects in T Cell Development 104
3.2 Mutations Affecting TCR Signaling 106
3.3 Defects in Costimulatory Pathways 122
3.4 Defects of Cytokine Signaling 126
3.5 Defects in Adhesion, Migration, or Cytoskeletal Organization 131
3.6 Defects in TFs/TF Regulation 139
3.7 Defects in Apoptotic Pathways 142
3.8 Defects in DNA Replication, Accessibility, Repair, and Telomere
Maintenance 146
3.9 Vesicular Trafficking and Protein Sorting 151
3.10 Defects of Ubiquitination 155
3.11 Defects of Glycosylation 155
3.12 Defects in Autophagy and Protein Turnover 158
3.13 Defects in Metabolic Pathways 159
3.14 Altered T Cell Effector Function in Complement Deficiencies 162
3.15 Unknown Mechanism 163
4. Current Challenges/Approaches and Future Considerations 164
References 167
Abstract
Proper regulation of the immune system is required for protection against pathogens
and preventing autoimmune disorders. Inborn errors of the immune system due to
inherited or de novo germline mutations can lead to the loss of protective immunity,
aberrant immune homeostasis, and the development of autoimmune disease, or
combinations of these. Forward genetic screens involving clinical material from patients
with primary immunodeficiencies (PIDs) can vary in severity from life-threatening dis-
ease affecting multiple cell types and organs to relatively mild disease with susceptibility
to a limited range of pathogens or mild autoimmune conditions. As central mediators of
innate and adaptive immune responses, T cells are critical orchestrators and effectors of
the immune response. As such, several PIDs result from loss of or altered T cell function.
PID-associated functional defects range from complete absence of T cell development
to uncontrolled effector cell activation. Furthermore, the gene products of known PID
causal genes are involved in diverse molecular pathways ranging from T cell receptor
signaling to regulators of protein glycosylation. Identification of the molecular and bio-
chemical cause of PIDs can not only guide the course of treatment for patients, but also
inform our understanding of the basic biology behind T cell function. In this chapter, we
review PIDs with known genetic causes that intrinsically affect T cell function with par-
ticular focus on perturbations of biochemical pathways.
1. INTRODUCTION
This theme has been at the centre of all my research…, both because of its intrinsic
fascination and my conviction that a knowledge of sequences could contribute
much to our understanding of living matter.
Frederick Sanger
2. PIDs
PIDs are most easily understood when they are caused by highly pen-
etrant single-gene errors. Clinical manifestations of PIDs usually present in
childhood and can be due to either de novo or hereditary mutations with
various Mendelian modes of inheritance (MOIs). Affected genes can be spe-
cifically required for a certain immune response, formation of a single immu-
nological cell type, or may more broadly affect a common cellular process
necessary for proper immunological function. As such, PIDs can present with
an extremely narrow clinical presentation, such as susceptibility to a single
class of pathogen, or with wide-ranging clinical immune phenotypes with
syndromic (nonimmune) features. The variants that cause PIDs are generally
highly deleterious to the function of the encoded protein and, as such, are
relatively rare (<0.1%) within a given population compared to less deleteri-
ous variants. This contrasts with the relatively common variants (0.1%) that
contribute to the susceptibility to more common immunological diseases
such as type 1 diabetes mellitus (T1DM) and inflammatory bowel disease
(IBD). Though the single-gene defects giving rise to PIDs tend to be severe,
there can be significant differences in penetrance (the proportion of individ-
uals with a disease genotype having the corresponding clinical phenotype)
and expressivity (the constellation and severity of clinical symptoms). The
International Union of Immunological Societies Expert Committee for Pri-
mary Immunodeficiencies keeps a continuously updated list of known PID
102 William A. Comrie and Michael J. Lenardo
genes, which, as of writing this review, has a total of 354 immunological dis-
eases with a known genetic cause, accounting for nearly 10% of all single gene
disorders that have been defined (http://www.iuisonline.org).
Despite the relative rarity of PIDs compared to other immunological dis-
orders, there are a multitude of benefits that can be gained by studying the
underlying genetic and biochemical mechanism of PID pathogenesis. First,
it provides an opportunity to gain novel insight into regulation of the
human immune system. Second, it can offer great benefit to the patients
who carry the burden of these disorders. Identification of the causal variant,
MOI, and mechanism of action may provide clinicians with guidance in
selecting a targeted therapy and allows for informed genetic counseling
to the family with critical information relevant to life decisions. Third, we also
gain scientific insights into the molecular pathways that mediate infectious
and autoimmune disease at the population level. Fourth, by genetically
“solving” PIDs, new immune genes have been discovered, new functions
of known genes have been elucidated, and knowing how genes affect human
immunology enables us to better annotate the human genome (Casanova,
Abel, & Quintana-Murci, 2013). Finally, a key benefit of studying PIDs
is understanding the variability of the causal genetic lesions generated by
random mutation in the human population which cannot be derived from
experimental animal models. These experiments of nature can lead to similar
clinical disease caused by completely different genes and demonstrate that
the same gene can cause various clinical phenotypes dependent on the type
of mutation. This can allow for identification of gene functions in the biolog-
ical context of both loss-of-function (LOF) and gain-of-function (GOF)
mutations, thus taking the study of a gene well past where the usefulness of
studying traditional knockout mice ends. Additionally, the constant exposure
of humans to environmental influences and a multitude of infectious agents
can help identify gene function that would not be immediately apparent in
simple inbred mouse models that are housed under specific pathogen-free
conditions.
Pathogenic DNA variants, excluding copy number variation or complete
deletion of the genetic locus, can be broken down into three categories: LOF,
hypomorphic mutations (partial LOF), and GOF. GOF mutations can be fur-
ther divided into two types: increased activity of a traditional function and
gain of a novel function. Fitting into one of these operational categories
are multiple types of DNA variants that include coding variants such as non-
sense, frameshift, canonical splice site mutations, loss of the initiation codon,
larger insertions or deletions, and missense mutations, as well as noncoding
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 103
3.2.2 CD8α
An autosomal recessive disease of recurrent bacterial and viral lung infections
is caused by biallelic deleterious variants in CD8α, encoding the CD8α chain
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 109
of the coreceptor for TCR interaction with class I MHC (OMIM 608957).
The CD8 and CD4 coreceptors are important for TCR signaling by binding
the constant portion of the MHCI and MHCII molecules, respectively, and
recruiting the lymphocyte-specific protein tyrosine kinase (Lck) to the TCR
complex where it initiates downstream signaling by phosphorylating CD3
chains and downstream kinases (Fig. 1). Interestingly, CD8α deficiency
may have incomplete penetrance. For example, two healthy siblings of
one patient have been identified as being homozygous for the same disease
allele (de la Calle-Martin et al., 2001; Mancebo et al., 2008). The reason for
this remains to be determined.
3.2.3 CD45
An autosomal recessive Tlow/NK+/B+ SCID phenotype (OMIM 608971)
is caused by biallelic LOF mutations in the gene encoding the protein
phosphatase CD45. Patients exhibit a combination of rash, fever, hepatos-
plenomegaly, diffuse lymphadenopathy, pneumonitis, pancytopenia, B cell
lymphoma, and neonatal cytomegalovirus (CMV) infections. Patient immu-
nophenotyping reveals very low αβ-positive T cells with normal or elevated
NK cells and normal or elevated B cells with defective germinal center forma-
tion and low Ig levels. The diffuse lymphadenopathy was B cell dependent.
Importantly, patient T cells failed to respond to mitogens (Kung et al.,
2000; Roberts et al., 2012; Tchilian et al., 2001). Interestingly, cd45/ mice
also show arrested T cell development at the transition from double positive
to single positive cells, phenocopying Lck-deficient mice. This appears to
be a gene dosage effect, because heterozygous mice have a moderate
decrease in single positive T cells compared to controls (Kishihara et al.,
1993). Further analysis revealed that in vitro B cell activation in response
to surface Ig-crosslinking to be defective in knockout cells as well as an
accumulation of pro-B cells, suggesting a B cell-intrinsic role for CD45
(Fleming, Milne, & Paige, 2004). These data suggest a possible unappre-
ciated B cell defect in CD45-deficient patients, though this has not been
previously described. In addition to the autosomal recessive disease, hetero-
zygous CD45 splice site mutations are associated with the development of
familial multiple sclerosis, though this association needs further investiga-
tion, and heterozygous LOF mutations occur with less than expected fre-
quency, possibly indicating an unrealized clinical condition associated with
CD45 haploinsufficiency (ExAC) (Jacobsen et al., 2000).
CD45 is a protein phosphatase known to positively regulate TCR
signaling by removing an inhibitory phosphate at Y505 on Lck (Burns,
110 William A. Comrie and Michael J. Lenardo
3.2.4 Lck
Lck is a tyrosine kinase that is recruited to the cytoplasmic tails of the
CD4 and CD8 coreceptors and is thus recruited to the TCR complex upon
coreceptor binding to MHC. Active Lck directly phosphorylates the
immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3
chains of the TCR complex. This is the earliest known phosphorylation
event upon TCR engagement and is essential for the antigen-mediated acti-
vation of T cells. Lck-dependent ITAM phosphorylation results in the
recruitment of zeta-chain-associated protein kinase 70 (ZAP-70) through
its Src homology 2 (SH2) domain and its subsequent phosphorylation and
activation by Lck (Salmond, Filby, Qureshi, Caserta, & Zamoyska, 2009).
Biallelic LOF mutations in LCK lead to an autosomal recessive PID
(OMIM 615758). In 2012, a single 15-month-old baby was discovered to
harbor a homozygous Lck missense mutation (L341P), which results in pro-
duction of an unstable and inactive Lck protein. TCR signaling was absent
in the patient and in a model system of Lck-deficient Jurkat T cells recon-
stituted with the Lck variant (L341P) (Hauck et al., 2012). The patient
suffered from diarrhea and failure to thrive, recurrent upper respiratory
infections, multiple modular skin lesions characterized by infiltration of
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 111
3.2.5 ZAP-70
ZAP-70 is a tyrosine kinase critical for TCR signaling. It is first recruited to
phosphorylated ITAMs on CD3ζ and is subsequently phosphorylated and
activated by Lck. Once activated, it phosphorylates linker for activation
of T cells (LAT) and SH2 domain containing leukocyte protein of
76 kDa protein (SLP-76), both critical adaptor molecules in the TCR sig-
naling pathway (Chan, Iwashima, Turck, & Weiss, 1992; Wang et al., 2010;
Zhang, Sloan-Lancaster, Kitchen, Trible, & Samelson, 1998). Biallelic LOF
mutations in ZAP-70 cause an autosomal recessive disease characterized as a
selective deficiency of CD8+ T cells due to abnormal thymic selection
(OMIM 269840) (Arpaia, Shahar, Dadi, Cohen, & Roifman, 1994; Elder
et al., 1994). Although the number of CD4+ T cells is normal in ZAP70-
deficient patients, their function is not. They exhibit abnormal calcium flux
in response to TCR engagement, demonstrating defective TCR signaling
(Chan et al., 1994). Clinically, ZAP70-deficient patients present early in life
with a history of recurrent infections including viral lung disease, candidiasis,
diarrhea, panhypogammaglobulinemia, and silent brain infarcts (Akar et al.,
2015; Arpaia et al., 1994; Chan et al., 1994; Elder et al., 1994; Liu et al.,
2017). Hypomorphic mutations with some residual kinase activity can result
in a milder phenotype with late-onset immunodeficiency associated with
skin and lung infections. These hypomorphic ZAP-70 patients have mod-
estly reduced T cell counts and reduced TCR-dependent signaling (Picard
et al., 2009a).
An additional autoimmune syndrome has recently been described due to
the unique combination of coinherited activating and hypomorphic muta-
tions in ZAP-70 (OMIM 617006) (Chan et al., 2016). The first of two sib-
lings born to nonconsanguineous parents developed nephrotic syndrome,
blistering skin disease, autoantibodies to clotting factor VIII resulting in
bruising and hemarthrosis, and inflammatory colitis. The second sibling
developed generalized bullous pemphigoid and failure to thrive due to
inflammatory colitis. In both cases, there was no evidence of altered T cell
numbers or immunodeficiency; however, successful hematopoietic stem cell
transplantation (HSCT) proved curative. Both patients possessed compound
heterozygous mutations in the ZAP-70 SH2 and kinase domains. The SH2
mutant did not associate with CD3ζ and resulted in diminished signaling
while the kinase domain mutant resulted in loss of autoinhibition and
enhanced ZAP-70, SLP76, and LAT phosphorylation after TCR stimula-
tion. This example is particularly interesting because the R360P mutation
in the catalytic domain enhanced kinase activity but was not capable of
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 113
causing a dominant disease by itself (the single mutation positive sister and
father were phenotypically normal). Apparently, the absence of WT protein
was necessary to allow the activating variant to induce disease, possibly
through preferential recruitment to CD3ζ in the presence of the SH2 variant
protein. It is possible that a more strongly activating mutation may cause a
similar disease in an autosomal dominant MOI.
3.2.6 RhoH
Ras homologue family member H (RhoH) is a hematopoietic-specific small
guanosine triphosphate hydrolase (GTPase), which, due to loss of amino
acid residues conserved in enzymatically active GTPases, can bind but
not hydrolyze GTP. Hence, it is generally considered to be constitutively
active (Li et al., 2002). A mutagenesis screen demonstrated that RhoH
was an essential negative regulator of the integrin LFA-1 (Cherry, Li,
Schwab, Lim, & Klickstein, 2004). Studies in rhoh/ mice showed that
RhoH is essential for T cell positive selection by directing the localization
of Lck and ZAP-70 to the immunological synapse (IS) as well as promoting
Lck’s interaction with and phosphorylation of CD3ζ-inducing downstream
signaling events (Chae, Siefring, Hildeman, Gu, & Williams, 2010; Dorn
et al., 2007; Gu et al., 2006). The interaction of ZAP-70 with RhoH is
mediated through a pseudo-ITAM motif in RhoH and influenced by
Lck activity. Interestingly, RhoH has opposite effects on Ras-related protein
1 (Rap1) and downstream integrin activation depending on the stimulus
with RhoH upregulating TCR-mediated signaling and downregulating
CXCR4-dependent signaling, possibly through the regulation of ZAP-70
localization (Baker et al., 2012).
Two siblings from a single consanguineous family have been described
with homozygous nonsense mutations in RhoH (Crequer et al., 2012).
T cells from the patients show reduced ZAP-70 phosphorylation, both at
baseline and upon TCR engagement. This almost completely abrogates
T cell proliferation in response to TCR stimulatory antibodies. In addition,
while these patients were not T cell lymphopenic, in contrast to rhoh knock-
out mice, they did have reduced naı̈ve T cells and enhanced T cell memory
and TEMRA populations, possibly as a consequence of lymphopenia-
induced proliferation. As in the mice, RhoH deficiency alters thymic
selection as patients display abnormal Vαβ repertoires. Despite the profound
signaling defect and loss of naı̈ve T cells, the patients’ clinical phenotype was
remarkably restricted, presenting with epidermodysplasia verruciformis, a
rare disorder characterized by increased susceptibility to ß-papillomaviruses.
114 William A. Comrie and Michael J. Lenardo
3.2.7 Itk
Interleukin-2-inducible T cell kinase (Itk) is a Tec family kinase that is
recruited to sites of TCR activation by binding PtdIns(3,4,5)P3 (PIP3)
through its pleckstrin homology (PH) domain. Once recruited, Itk interacts
with the SLP76/LAT complex and is phosphorylated and activated by Lck.
Following Lck-mediated phosphorylation, Itk then mediates its own
autophosphorylation and that of its downstream target phospholipase C,
gamma 1 (PLCγ) (Andreotti, Schwartzberg, Joseph, & Berg, 2010). Itk activ-
ity is required for T cell activation, effector function, and differentiation
through its phosphorylation of PLCγ and downstream diacylglycerol
(DAG) and calcium (Ca2+)-mediated signaling. Biallelic LOF mutations in
Itk result in a fatal EBV-associated lymphoproliferative disease associated with
increased risk of mononucleosis, Hodgkin’s lymphoma, lymphadenopathy,
splenomegaly, hypogammaglobulinemia, progressive CD4+ T cell loss, recur-
rent infections, autoimmune disorders, and cytopenias (OMIM 613011)
(Ghosh, Bienemann, Boztug, & Borkhardt, 2014; Huck et al., 2009; Linka
et al., 2012; Stepensky et al., 2011). Patient cells and patient-associated
Itk variants induce mild defects in Ca2+ flux downstream of TCR activa-
tion. Itk deficiency likely results in diminished CD8+ T cell ability to kill
EBV-infected B cells leading to the narrow clinical phenotype. Interest-
ingly, both Itk deficiency and MAGT1 deficiency, as discussed later, result
in diminished PLCγ activity and a selective susceptibility to EBV infection.
These two disorders also share a CD4+ T cell lymphopenia, suggesting Itk
and PLCγ are important for CD4+ T cell selection, activation, and/or long-
term survival.
and may have to do with the dynamics of extracellular Ca2+ entry caused
by the causal variant.
3.2.10 EVER2
Like calcium, other divalent cations including zinc (Zn2+) and magnesium
(Mg2+) are also important for T cell-mediated signaling (see MAGT1 defi-
ciency) (Li et al., 2011; Yu et al., 2011). Primary epidermodysplasia ver-
ruciformis, characterized by eruptions of wart-like protrusions caused by
human papilloma virus (HPV) infection, is caused by biallelic LOF in
EVER1 or EVER2, ER resident proteins predicted to be transmembrane
channels (OMIM 226400) (Horton & Stokes, 2014). T cells from EV
patients show diminished responses to mitogenic stimuli, though the mech-
anism is incompletely understood (de Pereira, Carrasco, Neto, Rady, &
Tyring, 2003; Prawer et al., 1977). EVER1 and EVER2 interact with the
Zn2+ transporter ZnT-1 and modulate its function to block Zn2+-dependent
TF activity (Lazarczyk et al., 2008). Interestingly, the HPV16 E5 protein
inhibited this interaction and increased Zn2+-dependent transcription, sug-
gesting this pathway is targeted by HPV to mediate its own survival or rep-
lication. In T cells, EVER1 and EVER2 proteins are expressed at baseline but
are rapidly downregulated following activation, correlating with a rise in
intracellular Zn2+ concentration (Lazarczyk et al., 2012). Consistent with
this, B and T cells from EVER2-deficient patients had increased intracellular
Zn2+. Altogether, this suggests that EVER proteins function to inhibit
ZnT-1 and limit intracellular Zn2+ concentrations. Loss of protein expres-
sion, whether during T cell activation or in EVER-deficient patients, abro-
gates this inhibition causing Zn2+ accumulation. As Zn2+ modulates early
TCR signaling through inhibition of src homology region 2 domain-
containing phosphatase-1 (SHP1) recruitment to the TCR, prolonged/ele-
vated Zn2+ concentrations at baseline may alter signaling or induce T cell
anergy. Further work is needed to determine the role of EVER proteins
in regulating Zn2+-dependent T cell activation and how elevated Zn2+ con-
centrations effect T cell function over the prolonged periods, though it is
tempting to speculate that altered Zn2+ homeostasis accounts for the
T cell proliferative deficiencies in EVER2-deficient patients.
3.2.11 SH2D1A
An excellent example of how PIDs can guide investigators to discover
new genes and signaling pathways is hemizygous LOF variants in the gene
SH2D1A and its product signaling lymphocytic activation molecule
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 121
3.2.12 PKCdelta
Biallelic LOF variants in PRKCD, the gene encoding protein kinase C delta
(PKCδ), cause an autosomal recessive disorder characterized primarily by
B cell hyperactivation, with mild defects in T cell activation (OMIM
615559) (Belot et al., 2013; Kuehn et al., 2013; Salzer et al., 2013a). Patients
suffer from recurrent infections, lupus-like autoimmunity with autoantibody
122 William A. Comrie and Michael J. Lenardo
3.3.2 CTLA4
Immune homeostasis is a balance between the ability to receive
costimulatory signals and dampen the immune response by inhibiting
CD28-dependent signaling as a form of checkpoint regulation. This is largely
accomplished through the immune checkpoint protein CTLA4 expressed
on Tregs and activated T cells. CTLA4 binds CD80 and CD86 with high
affinity, effectively competing with CD28 ligand binding. CTLA4 binding
removes CD80 and CD86 from the cell surface by transendocytosis to
dampen the T cell immune response (Sansom, 2015; Tivol et al., 1995;
Walker & Sansom, 2011; Waterhouse et al., 1995). Coding variants in
CTLA4 have long been identified as potential risk alleles in common auto-
immune disorders such as Graves’ disease, Celiac disease, T1DM, and
124 William A. Comrie and Michael J. Lenardo
systemic lupus erythematosus (Barreto et al., 2004; Nistico et al., 1996; Ueda
et al., 2003). More recently, an autosomal dominant disease, termed
“CTLA-4 haploinsufficiency with autoimmunity and infiltration” (CHAI)
disease has been described due to heterozygous LOF variants in CTLA4
(OMIM 616100) (Kuehn et al., 2014; Schubert et al., 2014). Like
CTLA4-deficient mice, patients develop a T cell lymphocytic infiltrative
disease in several tissues including intestines, lungs, bone marrow, central
nervous system, and kidneys with lymphadenopathy and splenomegaly asso-
ciated with reduced CTLA4 expression levels. On a cellular level, patient
Tregs express less FOXP3 and CD25 and are less inhibitory than control
Tregs while conventional T cells are hyperproliferative in response to anti-
genic stimulation. Importantly, this disease can be treated with CTLA4-Ig,
which replaces, pharmaceutically, the natural function of CTLA-4 in
patients (Lee et al., 2016). CTLA4 deficiency, like other forms of autoim-
mune lymphoproliferative disease (see below), is incompletely penetrant,
with only about 50% of mutation-bearing individuals showing clinically
appreciable disease despite reduced CTLA4 expression. Whether these clin-
ically asymptomatic individuals have protective variants in other genes or the
disease is precipitated by susceptibility genes or an immunological/environ-
mental event remains to be explored.
3.3.3 ICOS
Inducible T cell costimulatory (ICOS) is upregulated on the surface of acti-
vated T cells, particularly T follicular helper cells (Tfh), with structural and
sequence homology to CD28 and CTLA-4 (Hutloff et al., 1999). Ligation
of ICOS with an activating antibody provides a strong costimulatory signal
to responding T cells leading to enhanced proliferation, primarily through
PI3K recruitment to the YMFM motif in the cytoplasmic tail of ICOS
(Harada et al., 2003; Yong, Salzer, & Grimbacher, 2009). ICOS is par-
ticularly important for the development of T cell-dependent antibody
responses and the germinal center reaction through a combination of
ICOS-dependent Tfh formation, migration into the germinal center, and
costimulatory events necessary for the delivery of T cell help to GC B cells
(Dong, Temann, & Flavell, 2001; Wikenheiser & Stumhofer, 2016; Xu
et al., 2013; Yong et al., 2009). Biallelic LOF mutations in ICOS lead to
autosomal recessive combined variable immunodeficiency (CVID) with
recurrent bacterial infections, sinusitis, bronchiectasis, pneumonia, GI infec-
tions with diarrhea, hepatosplenomegaly, and in some cases malignancy cau-
sed by decreased class-switched and memory B cells, decreased serum
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 125
3.3.5 CD27/CD70
Stimulation of CD27, a member of the TNF family of receptors expressed
on T, B, and NK cell populations, by its ligand CD70 (expressed on B cells
and APCs) results in the activation of NF-κB and c-Jun N-terminal kinase
(JNK) resulting in enhanced effector and memory differentiation (Denoeud
& Moser, 2011; Hendriks et al., 2000). Biallelic LOF mutations in CD27
cause an EBV-associated lymphoproliferative disorder with symptoms vary-
ing from an asymptomatic memory B cell deficiency to EBV-driven
126 William A. Comrie and Michael J. Lenardo
3.4.2 IL7Rα
Biallelic LOF mutations in IL-7R alpha subunit result in an autosomal reces-
sive T/B+/NK+ SCID phenotype with absent peripheral T cells, opportu-
nistic infections, splenomegaly and lymphadenopathy, candida, pneumonia,
and diarrhea (OMIM 608971) (Puel, Ziegler, Buckley, & Leonard, 1998).
This defect likely occurs during thymic development during which IL-7 is
critical for survival and proliferation, though IL-7 is also essential for mature
T cell survival and homeostasis in the periphery (Giliani et al., 2005).
3.4.3 CD25
Biallelic LOF mutations in the alpha subunit of IL2RA (CD25), which com-
bines with IL2RB and CD132 to form a high-affinity IL-2 receptor, cause an
autosomal recessive immunodeficiency with autoimmunity (OMIM
606367) (Caudy, Reddy, Chatila, Atkinson, & Verbsky, 2007; Goudy
et al., 2013; Sharfe, Dadi, Shahar, & Roifman, 1997). Patients develop recur-
rent viral, bacterial, and fungal infections but also large-scale autoimmune
disease including lung inflammation and infiltration, hepatosplenomegaly,
enteropathy, eczema and dermatitis, and T1DM. Interestingly, these clinical
features combine IPEX-like disease with a T cell-specific immunodefi-
ciency. CD25 deficiency results in decreased RICD as well as reduced Treg
function because IL-2 is required for both Treg survival and effector function
(Barron et al., 2010; Pandiyan, Zheng, Ishihara, Reed, & Lenardo, 2007).
Additionally, patient T cells fail to make the immunosuppressive cytokine
IL-10 following TCR stimulation which may contribute to enterocolitis.
Loss of T cell homeostasis, Treg function, and IL-10 production may
account for the nonspecific T cell activation and expansion and IPEX-like
autoimmunity associated with CD25 deficiency. CD25 is also required for
TCR-induced proliferation, the absence of which leads to defective
antigen-specific responses and the recurrent infections associated with
128 William A. Comrie and Michael J. Lenardo
CD25 deficiency. Thus CD25 is critical for IL-2 regulation of both effector
and regulatory T cell function and overall control of the peripheral lymphoid
compartment (Willerford et al., 1995).
3.4.4 IL21/IL21R
Biallelic LOF mutations in the IL-21 (OMIM 615767) and the IL-21 recep-
tor (IL-21R) (OMIM 615207) cause a similar recessive immunodeficiency
characterized by recurrent respiratory tract infections, hepatitis, liver fibrosis,
recurrent diarrhea, septicemia, impaired B cell class switching, and impaired
T cell responses to candida antigens (Kotlarz et al., 2013; Salzer et al., 2014).
IL-21 signaling enhances T helper (Th)17 and Tfh differentiation while
inhibiting Treg differentiation, which could account for the T cell abnor-
malities, and is possibly related to the development of colitis (Leonard &
Wan, 2016; Tian & Zajac, 2016). IL-21 also enhances B cell class switching,
which leads to a B cell autonomous defect in humoral immunity in these
patients.
3.4.5 IL12RB1/IL-12B
IL-12 signaling is essential for the differentiation of naı̈ve T cells into Th1
cells. Biallelic LOF mutations in the beta subunit of the IL-12 receptor
(IL-12RB1) (OMIM 614891) or the p40 subunit of IL-12 (IL-12B)
(OMIM 614890) result in a clinically limited PID with a selective suscep-
tibility to mycobacteria, candida, and salmonella infections (Altare et al.,
1998a, 1998b; de Jong et al., 1998; Picard et al., 2002). Patients with
IL-12B deficiency do not produce IL-12 or the Th1 cytokine IFNγ which
is necessary for the control of intracellular bacterial infections. IL-12RB-
deficienct patients have reduced Th1 responses and IFNγ production upon
stimulation. IL-21RB1 and IL-12B-deficient patients also had defects in
IL-17 producing Th17 cell formation, thus accounting for the recurrent
fungal infections (de Beaucoudrey et al., 2008). Importantly, the nature
of the mutation in this pathway is critical for treatment, because only
IL-12 deficient, and obviously not IL-12RB1 deficient, patients can be trea-
ted by the administration of exogenous IL-12.
3.4.6 TYK2
An autosomal recessive immunodeficiency with recurrent respiratory, viral,
mycobacterial, and intracellular bacterial infections is caused by LOF muta-
tions in tyrosine kinase 2 (TYK2), the JAK family member kinase associated
with signaling downstream of IFNα, IL-12, IL-10, and IL-23, among others
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 129
(OMIM 611521) (Kreins et al., 2015; Minegishi et al., 2006; Watford &
O’Shea, 2006). As with mutations in other JAK/STAT proteins, the com-
plex and varied patient phenotypes likely result from defects in signaling
from multiple cytokine receptors that rely on TYK2. Thus, the viral and
bacterial susceptibility of TYK2-deficient patients seem attributable to the
loss of IFNα and IL-12 signaling, respectively. Indeed Tyk2-deficient cells
have reduced IFNα, IL-10, and IL-12 receptor expression and diminished
IFNα, IL-10, IL-23, and IL-12 signaling. Importantly, patients have dimin-
ished IL-12-dependent IFNγ production, but this was not as severe as in
IL12R-deficient patients. Perhaps there is a degree of compensation by
other JAK family members. Together, this indicates that TYK2 deficiency
is indeed an amalgamation of incomplete signaling defects downstream of
multiple cytokine receptors.
3.4.7 JAK1
JAK1 pairs with JAK3 to mediate signaling downstream of the common-
gamma chain cytokine receptors (OMIM 147795) (Lin & Leonard,
2017). Three patients with JAK1 mutations from a single kindred presented
with atopic dermatitis, allergies, hepatosplenomegaly, autoimmune thyroid
disease, and failure to thrive caused by an autosomal dominant JAK1 muta-
tion (Del Bel et al., 2017). The causal A634D missense mutation lies within
the JAK1 inhibitory domain and enhances phosphorylation of STAT3 in
T cells following IL-6 stimulation. Patients treated with ruxolitinib, a
JAK1/2 inhibitor, showed marked clinical improvement after a month of
treatment, again emphasizing the importance of understanding the molec-
ular cause of disease in designing an individualized medical intervention (Del
Bel et al., 2017).
3.4.8 JAK3
Biallelic LOF mutations in JAK3 cause an autosomal recessive SCID
with recurrent upper respiratory tract infections, diarrhea, meningitis, absent
peripheral lymph nodes, reduced T and NK cell numbers, reduced TCR-
dependent T cell activation, and B cell activation deficiencies with hyp-
ogammaglobulinemia (OMIM 600802) (Macchi et al., 1995; Russell et al.,
1995). As JAK3 is the sole JAK responsible for signaling through CD132,
JAK3 deficiency largely phenocopied CD132 X-linked SCID (Lin &
Leonard, 2017). In patient T cells, JAK3 deficiency results in abrogation of
STAT protein phosphorylation after stimulation with all tested gamma chain
cytokines, thus confirming the interrelated nature of these two PIDs.
130 William A. Comrie and Michael J. Lenardo
3.4.9 STAT3
Deleterious variants in STAT3 have been linked to several separate PIDs.
The first is caused by dominant negative (DN) mutations in STAT3
resulting in an autosomal dominant hyper-IgE syndrome (Job (pronounced
with a long “o”) syndrome, OMIM 147060). Clinical features of Job syn-
drome include eczema, skin abscesses, Staphylococcus infection, recurrent
fungal infections, increased IgE, and eosinophilia (Holland et al., 2007;
Minegishi et al., 2007). Three concurrent reports demonstrated that DN
STAT3 mutations specifically impaired the development and function of
Th17 cells (de Beaucoudrey et al., 2008; Ma et al., 2008; Milner et al.,
2008). Naı̈ve T cells from Job syndrome patients were also defective in pro-
liferation and differentiation into central memory T cells which leads to poor
suppression of latently infected EBV and Zoster viruses (Siegel et al., 2011).
The second PID caused by STAT3 variants is an autosomal dominant disease
caused by activating STAT3 mutations which causes an infantile onset mul-
tisystem autoimmune disease (OMIM 615952) (Flanagan et al., 2014;
Milner et al., 2015). Patients variably suffer from interstitial pneumonitis,
autoimmune enteropathy, arthritis, eczema, T1DM, hypothyroidism, auto-
immune cytopenias, hepatosplenomegaly, lymphadenopathy, and large
granular lymphocytic T cell leukemia. Tregs from patients are reduced in
number and functional markers, suggesting that decreased Treg function
may contribute to the autoimmune disease. Interestingly, while STAT3
activity was increased, stimulation-dependent phosphorylation of STAT1
and STAT5 were diminished. The STAT1 and STAT5 defects are likely
due to tachyphylaxis mediated by STAT3-driven expression of suppressor
of cytokine signaling 3, thus dampening the activation of other STATs.
Interestingly, pharmacological blockade of IL-6, which signals though
STAT3, resulted in dramatic clinical improvement. Thus, the patient phe-
notype is due to an increase in STAT3 signaling and a decrease in sensitivity
to other cytokines. A decrease in STAT5 activation downstream of IL-2
could explain the overlap in Treg phenotypes, which depend on IL-2 sig-
naling, in patients with STAT5b deficiency and activating STAT3 variants
(see below). Given the activating nature of the STAT3 variants in this dis-
ease, and the success of IL-6 blockade, ruxolitinib likely represents a ther-
apeutic option for these patients.
3.4.10 STAT5b
Homozygous LOF mutations in STAT5b (activated downstream of IL-2,
IL-4, and various growth hormones) are associated with an autosomal
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 131
3.5.1 RASGRP1
Homozygous LOF mutations in RAS guanyl releasing protein 1
(RASGRP1) cause recurrent bacterial and viral infections with low CD4+
T cells, B cells, and NK cells, and an inverted CD4+/CD8+ ratio with
132 William A. Comrie and Michael J. Lenardo
primarily effector or memory CD8+ T cells (Mao et al., 2017; Salzer et al.,
2016). RASGRP1 is a Ras GEF with a DAG-binding domain that is
highly expressed in hematopoietic lineages (OMIM 603962). Studies in
knockout mice show reduced peripheral T cell populations due to defec-
tive Ras and extracellular signal-regulated kinase (ERK) activation leading
to diminished proliferation and impaired thymocyte development (Dower
et al., 2000). Conversely, overexpression of RASGRP1 enhanced ERK
and Rac activation in Jurkat T cells, further solidifying the importance
of RASGRP1 in this pathway (Ebinu et al., 2000). Fitting with this,
CD4+ and CD8+ T cells from RASGRP1 patients had intact calcium flux
responses but diminished ERK activation, CD69 upregulation, and pro-
liferation upon TCR-induced activation (Mao et al., 2017; Salzer et al.,
2016). Additionally, patient T cells had defective actin polymerization
and reduced retrograde flow in migrating lymphocytes, which was asso-
ciated with defects in RhoA activation and was reversible by lenalidomide
treatment, which targets this pathway.
3.5.2 DOCK2
Dobbs et al. identified biallelic LOF mutations in dedicator of cytokinesis 2
(DOCK2), which encodes a hematopoietic-specific RAC1 GEF, as a cause
of early onset and severe viral and bacterial infections (OMIM 616433)
(Dobbs et al., 2015; Fukui et al., 2001). Rac1-GTP loading, chemotaxis,
and actin polymerization downstream of chemokine receptor activation
were defective in patient T cells. Perhaps more interestingly, patient NK cells
had defective mitogen activation protein kinase kinase (MEK) and ERK sig-
naling. These results are intriguing as DOCK2 and Rac1 are not known to
directly affect the MEK/ERK pathway, which may suggest that DOCK2
acts as a GEF for Ras, like RASGRP1 (see above). Additionally, patient
NK cells did not produce IFNγ after cytokine stimulation while patient
fibroblasts did not produce interferon alpha (IFNα) following viral infection.
These results may reflect altered intracellular trafficking of cytokine receptors
and interferon molecules, since DOCK2 plays an essential role in molecular
trafficking through regulation of microtubule dynamics (Tanaka et al.,
2007). As DOCK2 activity is regulated by its association with ELMO1,
and cannot assert its GEF activity in the absence of the Rac1/ELMO1/
DOCK2 trimeric complex, it is possible that a similar PID could arise
through LOF mutations in ELMO1 (Brugnera et al., 2002; Sanui et al.,
2003; Stevenson et al., 2014).
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 133
3.5.3 DOCK8
Biallelic LOF mutations in another DOCK-180-related protein (DOCK8)
cause a PID characterized by recurrent sinopulmonary and cutaneous bac-
terial and viral infections, and elevated IgE levels with severe atopy and ana-
phylaxis termed DOCK8 immunodeficiency syndrome (OMIM 243700)
(Zhang et al., 2009). Patients have extremely low T and NK cell counts with
poor ex vivo CD8+ T cell proliferation. This progressive loss of T and NK
cells is due to both the aforementioned proliferative defects, and a failure in
DOCK8-deficient T and NK cellular integrity when confined in a 3D envi-
ronment, such as dermal tissue or an artificial collagen matrix, leading to cell
elongation, nuclear deformation, and a form of cell death called cytothripsis
(Zhang et al., 2014a). Interestingly, while DOCK8 and CDC42 knock-
down resulted in a similar phenotype, knockdown of Wisckott–Aldrich
syndrome protein (WASP), the main regulator of ARP2/3 downstream
of CDC42, did not. This suggests that maintenance of cellular integrity in
confined spaces is an actin-independent function of DOCK8/CDC42.
Indeed, knockdown of PAK1/2, another downstream effector of CDC42,
caused enhanced cytothripsis. Cellular elongation of DOCK8-deficient cells
is accompanied by a deformation of the nucleus, suggesting that the target of
PAK1/2 was critical for maintaining nuclear rigidity under mechanical stress.
It is possible that PAK1/2, and by extension DOCK8, is regulating interme-
diate filaments such as lamins and vimentins to maintain nuclear integrity/
rigidity. The lack of a chemotactic defect in DOCK8 T cells may also indicate
that there is another GEF capable of regulating CDC42 and WASP activation
as these are hallmarks of Wiskott–Aldrich syndrome (WAS), see below.
DOCK8 may also regulate a specific subset of CDC42 effectors by acting
as both a GEF and a molecular scaffold that bridges CDC42 to downstream
effectors. DOCK8 and DOCK2 deficiencies also serve to highlight the great
variety of immunodeficiencies that can arise from alterations to cytoskeletal
dynamics, as defects in either a RAC or CDC42 GEF can cause such varied
cellular and clinical phenotypes.
3.5.4 Coronin 1A
One aspect of the actin cytoskeleton in lymphocytes is its highly dynamic
nature, both during migration and IS formation. In order to maintain this
highly dynamic structure actin polymerization must be accompanied by
turnover of old F-actin filaments and generation of G-actin monomers.
The coronin family of proteins plays a role in both functions by promoting
or substituting for ARP2/3 to initiate a highly flexible branched actin
134 William A. Comrie and Michael J. Lenardo
3.5.5 WASP
WASP is a hematopoietic-specific activator of the ARP2/3 complex which
signals downstream of CDC42 (Thrasher, 2002). It is a good example of a pre-
viously unknown protein that was identified and functionally characterized
through the study of PIDs. WASP was originally identified as the affected pro-
tein in WAS through a positional cloning strategy (Derry, Ochs, & Francke,
1994). Mutations in the WAS gene lead to three different X-linked recessive
disorders: WAS, severe congenital neutropenia, and X-linked thrombocyto-
penia. We will discuss WAS in more detail. Depending on the causal variant,
WAS can be associated with eczema, thrombocytopenia, recurrent infections,
bloody diarrhea, autoimmunity, and hematopoietic malignancy. This disease
usually follows a fatal course without HCST due to defects in multiple hema-
topoietic lineages including T, B, and NK cells (OMIM 301000). WASP is
critical for T cell development, as well as multiple actin-mediated cellular
functions, including microvilli formation (important for slow rolling and
adhesion on endothelium), migration, actin polymerization, protein recruit-
ment to the IS, and TCR-mediated cellular activation/proliferation (Bouma,
Burns, & Thrasher, 2009; Thrasher & Burns, 2010). Of note, WASP is
activated downstream of CDC42, for which DOCK8 is a critical GEF and
activator. While the patients share some clinical overlap, DOCK8 cells are
capable of normal chemotaxis suggesting intact cytoskeletal responses in these
cells, either compensated by another CDC42 GEF or by RAC1-mediated
activation of the WASP homologue, WAVE2. WASP-deficient T cells are
not known to exhibit the stretched T cell morphology in 3D environments
characteristic of DOCK8 T cells which supports the idea that DOCK8 defi-
ciency involves nonactin-dependent pathogenic mechanisms.
3.5.6 WIP
WIP (WASP-interacting protein) was originally identified in a yeast two-
hybrid screen for WASP-binding partners and induces actin polymerization
in lymphoid cells when overexpressed (Ramesh, Anton, Hartwig, & Geha,
1997). WIP both regulates the localization of WASP and protects it from
calpain-mediated cleavage and degradation (Chou et al., 2006). WIP, like
WASP, regulates actin dynamics during T cell activation and is essential
for both CD3/28-mediated CD25 upregulation and proliferation (Anton
et al., 2002; Volkman, Prehoda, Scott, Peterson, & Lim, 2002). Given that
a large percentage of WAS mutations occur within the WIP-interacting
domain of WASP, it is perhaps unsurprising that homozygous WIP LOF
variants cause a WAS-like immunodeficiency characterized by eczema,
136 William A. Comrie and Michael J. Lenardo
papulovascular lesions on the scalp, ulcerative lesions on the hard palate and
tongue, thrombocytopenia, and respiratory distress (OMIM 614493) (Lanzi
et al., 2012). WIP-deficient patients have reduced CD8+ T cell numbers and
defective T and NK cell function. Importantly, both WIP and WASP pro-
teins were undetectable in patient cells, and exogenous expression of WIP
was able to rescue WASP expression—showing that they are obligate part-
ners in a stable protein complex. WIP deficiency is thus an excellent example
of how mutations in different proteins in the same pathway can present with
identical clinical phenotypes.
3.5.7 Moesin
Hemizygous mutations in the X-linked gene encoding the Ezrin/Radixin/
Moesin (ERM) family member moesin were identified in seven affected
males from five kindreds suffering from profound T, B, and NK cell
lymphopenia, hypogammaglobulinemia, monocytopenia, neutropenia, poor
vaccine responses, bacterial infections, and zoster virus infections (OMIM
300988) (Delmonte et al., 2017; Lagresle-Peyrou et al., 2016). These variants
lead to either unstable protein or truncated protein products in affected indi-
viduals. Moesin is involved in linking plasma membrane proteins to the
underlying actin cytoskeleton through its FERM and actin-binding domain,
respectively (Fehon, McClatchey, & Bretscher, 2010). This can control the
mobility, localization, and function of key immunological regulators, such as
the intercellular cell adhesion molecule (ICAM1) (Comrie, Li, Boyle, &
Burkhardt, 2015). In addition, moesin regulates cortical actin networks
and polarization of human T cells in response to CXCL12 (Brown et al.,
2003). Moesin-deficient patient T cells are defective in antigen-induced pro-
liferation. While conjugate formation and actin polymerization at the IS were
generally intact, the authors did not look at the dynamic redistribution of
ERM-binding partners during IS formation leaving open the possibility of
more subtle defects in IS formation. Additionally, patient T cells had defec-
tive chemotaxis and enhanced integrin-mediated adhesion due to increased
integrin expression and affinity maturation, though exactly how moesin reg-
ulates these integrin changes have not been worked out. Accompanying the
patient lymphopenia was a relative loss of naı̈ve T cells and an expansion of
senescent T cells, possibly due to lymphopenia-induced expansion. It should
be noted that senescent cells activate poorly, so whether the poor expansion
of T cells from PBMCs represents a true signaling defect or a byproduct of
increased T cell senescence is not currently known. The identification of
moesin-deficient patients demonstrates the sometimes discordant phenotypes
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 137
between mouse and man, as studies in moesin knockout mice have shown
relatively mild immunological defects, likely due to redundant function of
the related ezrin protein (Hirata et al., 2012). Nevertheless, moesin deficiency
resulted in reduced thymic and bone marrow egress of T and B cells causing
lymphopenia in mice. In humans, who may rely more on moesin, defects in
migration from lymphoid organs may be compounded which could explain
the severe lymphopenic status if hematopoietic progenitors cannot migrate to
or from the thymus efficiently.
3.5.8 CXCR4
Activating mutations in the chemokine receptor CXCR4 cause an auto-
somal dominant disorder called WHIM syndrome (WHIMS) characterized
by peripheral neutropenia due to retention in bone marrow, chronic HPV
infection with skin warts, upper respiratory tract infections, and hyp-
ogammaglobulinemia (OMIM 193670). Patient mutations reduce CXCR4
internalization following ligand engagement, thus leading to enhanced stim-
ulation by and migration toward CXCL12 (Balabanian et al., 2005;
Hernandez et al., 2003; Lagane et al., 2008). As mentioned before, T cells
are highly migratory and must also form a stable IS to become activated
and exert effector functions. Thus, T cells must balance the two discordant
functions of chemokine-driven “go” signals and TCR-mediated “stop” sig-
nals to function properly. While T cells from normal donors preferentially
reduced their migratory behavior following stimulation by antigen-loaded
APCs, WHIMS-T cells maintain their migratory behavior and will form
shorter T/APC interactions (Kallikourdis et al., 2013). As T cells can receive
chemokine-driven costimulatory signals and CXCL12 mediates aberrant
costimulation of WHIM B cells, it will be interesting to see if WHIM
T cells are hypersensitive to chemokine-driven costimulation (Molon
et al., 2005; Roselli et al., 2017). The outcome of T cell antigen stimulation
and the course of the T cell immune response in WHIMS are thus likely
determined by the combined effects of enhanced chemokine-driven costi-
mulatory signaling and reduced APC dwell time.
3.6.1 FOXP3
A deadly X-linked autoimmune disorder characterized by early onset and
severe IBD/colitis, candidiasis, eczema, atopy, T1DM, and hypothyroidism,
autoimmune cytopenias, lymphadenopathy, and various other autoimmune
conditions is caused by Forkhead box P3 (FOXP3) deficiency, the causative
gene for a similar phenotype in scurfy mice (Bennett et al., 2001; Brunkow
et al., 2001). This condition, termed IPEX or XLAAD disease (OMIM
304790), allowed for the first characterization of the FOXP3 gene, prior
to understanding its role in immune function (Chatila et al., 2000). FOXP3
is now well understood to act as the master TF initiating the development
and maintenance of regulatory T cells (Hori, Nomura, & Sakaguchi, 2003).
Tregs, recruited to the sites of conventional T cell activation downmodulate
the immune response through multiple effector pathways including IL-2
consumption and CTLA-4-mediated inhibition of CD28 ligands on APCs,
among others (Josefowicz, Lu, & Rudensky, 2012). Tregs can also promote
protective immune responses, especially to certain classes of fungi, which
accounts of the candidiasis that occurs in IPEX disease (Pandiyan et al.,
2011). Interestingly, IPEX disease shares several clinical similarities, partic-
ularly colitis, with PIDs associated with other Treg defects such as CTLA-4
deficiency, IL-2 signaling defects, and BACH2 deficiency (see below) thus
highlighting the critical nature of this cell population to the control of
human autoimmunity.
3.6.2 BACH2
Heterozygous mutations in transcriptional repressor BTB and CNC homol-
ogy 2 (Bach2) cause a syndrome of early-onset colitis, splenomegaly,
140 William A. Comrie and Michael J. Lenardo
3.6.3 BCL11B
An autosomal dominant disease caused by a heterozygous DN variant in
B cell CLL/lymphoma 11B (BCL11B) causes a leaky SCID phenotype with
syndromic features (OMIM 617237). Immunologically the patient had
T cell lymphopenia, absent TREC formation and naı̈ve CD4+ T cell popu-
lations, and impaired proliferative responses (Punwani et al., 2016). BCL11B
encodes for a TF with multiple roles in T cell formation and function
(Avram & Califano, 2014). BCL11B positively regulates T cell lineage com-
mitment while inhibiting pluripotency during thymopoesis, a process that
may determine the T cell-specific immunological phenotype. BCL11B also
aids in the expansion of T cells in the periphery and induction of effector
function, accounting for decreased patient T cell proliferation to mitogen.
3.6.5 RELA
Badran et al. and Comrie et al. have described an autosomal dominant
disorder caused by p65/RELA haploinsufficiency (Badran et al., 2017;
Comrie et al., 2018). In the first report, the authors describe colitis and
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 141
3.6.6 CARD11
CARD11 mutations cause both autosomal recessive (OMIM 615206) and
autosomal dominant (OMIM 616452) disorders due to LOF and GOF
mutations, respectively (Zhang et al., 2017). GOF mutations result in spon-
taneous CARD11 aggregation and NF-κB activation in B and T cells in
B cell expansion with NF-κB and T cell anergy (BENTA) disease (Snow
et al., 2012). While these GOF variants lead to spontaneous B cell activation,
they result in diminished T cell responsiveness to TCR-mediated stimula-
tion in the absence of appropriate costimulation, a form of stimulation that is
known to cause T cell anergy. Recently an autosomal dominant PID asso-
ciated with CARD11 hypomorphic mutations that cause dominant interfer-
ence with the WT CARD11 allele-dependent activation of NF-κB has been
described (OMIM 617638) (Ma et al., 2017). These patients presented with
severe atopic dermatitis, allergies, elevated IgE, molluscum contagiosum
infection, decreased B cell numbers, and defective T cell activation.
Decreased NF-κB activation leads to reduced CD25 upregulation and pro-
liferation following TCR-mediated T cell stimulation. Why this disease
results in a different clinical phenotype than biallelic CARD11 LOF disease
remains to be seen, though the DN mutations may allow for some residual
CARD11 activity, possibly with altered kinetics, while LOF variants result
in complete loss of CARD11-dependent NF-κB induction downstream of
antigen receptors.
142 William A. Comrie and Michael J. Lenardo
3.7.3 XIAP
In a disease whose molecular pathogenesis is related to that of ALPS, LOF
mutations in X-linked inhibitor of apoptosis (XIAP) cause an X-linked
recessive lymphoproliferative syndrome with recurrent infections, EBV
viremia, fever, hemophagocytic lymphohistiocytosis, IBD, and loss of
NKT cells (OMIM 300635) (Aguilar & Latour, 2015; Rigaud et al.,
2006; Worthey et al., 2011). XIAP is thought to act by inhibiting caspase
function downstream of death receptor engagement and can block FAS-
mediated apoptosis (Bratton, Lewis, Butterworth, Duckett, & Cohen,
2002; Holcik & Korneluk, 2001). Functionally, XIAP-deficient patient cells
show increased apoptosis mediated by FAS, TNSF10, and RICD. Thus,
XIAP deficiency results in an inability to control infection through increased
FAS-mediated death of effector cells, and enhanced RICD-mediated death
of antigen-specific cells leading to functional immunodeficiency. XIAP also
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 145
3.7.4 STK4
Serine/threonine-protein kinase 4 (STK4) is a proapoptotic and antip-
roliferative kinase best known for its involvement in the Hippo signaling
pathway necessary for organ size control (Harvey, Zhang, & Thomas,
2013). This is accomplished by initiating a cellular signaling cascade that ulti-
mately results in the phosphorylation and degradation of the transcriptional
coactivators YAP/TAZ and loss of their proproliferative and antiapoptotic
functions. Additionally, STK4 is required for the phosphorylation and
activation of LC3 during autophagy, thus allowing for the fusion of
autophagosomes with lysosomes (Wilkinson et al., 2015). Biallelic LOF
mutations in STK4 cause an autosomal recessive PID characterized by
atrial septal defects, progressive loss of T and B cells resulting in T/B
lymphopenia, and intermittent neutropenia leading to the development
of recurrent viral, bacterial, and fungal infections (OMIM 614868)
(Abdollahpour et al., 2012). Fas- and staurosporine-induced apoptosis in
T cells and neutrophils, respectively, was dramatically increased in patient
cells compared to controls. This was associated with loss of plasma mem-
brane potential and decreased Forkhead box 03 protein (Foxo3) expres-
sion. As STK4 phosphorylation, activation, and stabilization of Foxo3
are critical for the protection of naı̈ve T cells from the damaging effects
of reactive oxygen species (ROS) in mice, it is likely that STK4 regulation
of Foxo3 is a critical regulator of the human disease (Choi et al., 2009).
Additionally, STK4-deficient patient T cells do not divide well, primarily
due to a massive increase in apoptosis associated with TCR stimulation, as
well as decreased Bcl2 and Foxo1 expression (Nehme et al., 2012).
Together, this suggests that STK4 deficiency results in increased T cell
apoptosis through regulation of STK4 targets outside of the Hippo path-
way, where STK4 normally promotes cell survival by activating Foxo3 and
inducing antiapoptotic and anti-ROS target genes. Notably, activation of
the Hippo pathway in T cells and induction of LC3 activation was not
described in any of these studies, and altered Hippo signaling or decreased
autophagy cannot be ruled out in this disease without further investigation.
Interestingly, STK4 is most highly expressed in naı̈ve T cells, which
implies its loss may sensitize cells to RICD and Fas-mediated apoptosis
in activated T cells as part of the normal immune response.
146 William A. Comrie and Michael J. Lenardo
3.8.1 POLEε
DNA polymerase epsilon (POLEε), a DNA polymerase composed of
four subunits, synthesizes the forward strand during conventional DNA
synthesis. Homozygous LOF mutations in POLE1, the catalytic subunit
of POLEε, cause a syndromic immunodeficiency with facial dysmorphism,
livedo, and short stature (FILS syndrome, OMIM 615139) (Pachlopnik
Schmid et al., 2012). Immunologically, patients suffer from recurrent upper
respiratory tract infections, pulmonary infections, bronchiectasis, and
bacterial meningitis. Patients have decreased B cell and immunoglobulin
levels, and a diverse T cell repertoire, but low naı̈ve T cell counts and
decreased T cell proliferation. Patient T cells proliferate poorly in response
to TCR stimulation with fewer cells entering S phase, likely due to stalled/
slow DNA replication. Unlike other cell types, T and B cells express more
POLEε than POLEδ, a related DNA polymerase, suggesting that the T and
B cell specificity of this immunodeficiency is a result of a cell-specific
dependence on POLEε. Biallelic LOF mutations in the second subunit
of POLEε, POLE2, have been described in a patient with facial dysmorph-
isms, combined immunodeficiency, and autoimmunity (Frugoni et al.,
2016). The patient suffered from omphalitis, erythroderma, recurrent
respiratory tract infections, T1DM, hepatomegaly, and hypothyroidism
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 147
3.8.3 MYSM1
Myb like, SWIRM and MPN domain 1 (MYSM1) is an essential compo-
nent of an H2A deubiquitinase complex that coordinates histone H1 disas-
sociation and DNA accessibility, thus allowing for transcription initiation
and elongation (Bahrami et al., 2017). Homozygous LOF mutations in
MYSM1 cause a syndrome of progressive bone marrow failure, immunode-
ficiency, and developmental abnormalities. Immunologically, patients suffer
from recurrent respiratory tract infections, with virtually absent mature and
class-switched B cells, and reduced T and NK cells. Furthermore, T cells
failed to proliferate robustly in response to mitogenic challenge (Alsultan,
Shamseldin, Osman, Aljabri, & Alkuraya, 2013; Bahrami et al., 2017; Le
Guen et al., 2015). MYSM1-deficient cells have increased p38 activation,
cell cycle arrest, and increased apoptosis, presumably due to altered tran-
scriptional activity. In one patient, a spontaneous genetic reversion caused
recovery of all affected hematopoietic lineages, suggesting a strong survival
advantage to WT cells over mutant cells. The exact genetic targets regulated
by MYSM1 remain to be identified and may shed light onto the mechanism
by which MYSM1 deficiency results in increased p38-induced apoptosis.
148 William A. Comrie and Michael J. Lenardo
3.8.4 ATM
Biallelic LOF mutations in ataxia–telangiectasia mutated (ATM) serine/
threonine kinase results in ataxia–telangiectasia (AT), characterized by cer-
ebellar ataxia, telangiectasia, immune defects, and malignancy (OMIM
208900). ATM is recruited to, and activated by, sites of DNA double-strand
breaks and is critical for the DNA damage response comprising inhibition of
cell cycle progression, DNA repair, and apoptosis. The immune defects
accompanying ATM deficiency include thymic hypoplasia, lymphopenia,
reduced T cell numbers, and reduced B cell differentiation (Chopra et al.,
2014; Staples et al., 2008). This is likely due to an inability to respond to
double-strand breaks that occur during thymopoesis and T cell selection,
resulting in apoptosis of T cell progenitors. Interestingly, AT patients present
with a relative increase in γδ T cells compared to αβ T cells (Carbonari et al.,
1990). This may reflect a less severe requirement of γδ T cells for ATM dur-
ing development, though this remains to be seen.
3.8.5 Nibrin
Nibrin (NBN) deficiency results in the autosomal recessive disorder Nijme-
gen breakage syndrome, which is associated with recurrent pneumonia, GI
infections, urinary tract infections, with reduced T cell numbers (OMIM
251260) (Varon et al., 1998). NBN, a component of the Mre11-Rad50-
Nbs1 (MRN) complex, is critical for the response to DNA damage and
maintenance of chromosomal integrity and telomere length (Lamarche,
Orazio, & Weitzman, 2010). Interestingly, NBN activates both ATR and
ATM by phosphorylation during DNA damage responses, placing it
upstream of ATM in the DNA damage response pathway (Lee & Paull,
2004; Stiff et al., 2005). Consistent with this, Nijmegen breakage syndrome
shares similar features to both AT and Seckel syndrome 1, an autosomal
recessive disease characterized by multiple developmental abnormalities,
but no known immunological features, due to hypomorphic ATR variants.
Given the related nature of ATM and ATR kinases, and their respective
roles in DNA damage responses, it is curious as it why ATM and NBN,
but not ATR, deficiencies result in immunological deficiencies.
3.8.6 SMARCAL1
Biallelic LOF variants in SWI/SNF related, matrix-associated, actin-
dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) cause
an autosomal recessive disease characterized by several immunological
defects including neutropenia, lymphopenia, and cytopenias with decreased
T cell numbers and absent mitogenic responses, largely phenocopying
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 149
3.8.7 NSMCE3
Biallelic LOF variants in NSMCE3 cause an autosomal recessive syndrome
immunologically characterized by thymic hypoplasia, recurrent pulmonary
infections, and eczema (OMIM 617241) (van der Crabben et al., 2016).
NSMCE3-deificient patients have severely reduced T cell numbers, with
reduced T cell responses to multiple mitogenic and recall response stimuli.
NSMCE3 is a critical component of the SMC5/6 DNA repair complex and
supports mitotic proliferation. Defects in both functions likely contribute to
the observed T cell defect, though the exact stages of T cell development and
T cell activation that are affected remain to be elucidated.
It is interesting that not all genetic disorders caused by defects in DNA
repair mechanisms are accompanied by a T or B cell-mediated immunode-
ficiency. Gene mutations affecting many members of the Fanconi anemia
complex cause a bone marrow failure syndrome but are not associated with
decreased T cell counts or function. Similarly, LOF variants in the gene
ERCC6L2 which encodes a novel DNA repair factor, termed Hebo, cause
a bone marrow failure syndrome without an appreciable T or B cell deficit
(Tummala et al., 2014; Zhang et al., 2016). This would suggest that there is a
special role for the ATM checkpoint kinase pathway in mediating T cell
development or function, given the majority of defects in DNA damage
response that cause T cell deficiency fall within this pathway.
3.9.1 HPS2
An autosomal recessive form of Hermansky–Pudlak syndrome with immu-
nodeficiency, including recurrent lung infections, recurrent bacterial infec-
tions, thrombocytopenia, with neutrophil, NK, and CTL functional defects
(HPS2) is caused by biallelic LOF mutations in AP3B1 encoding the beta-
3A subunit of the adaptor protein (AP)-3 complex (OMIM 608233)
(Dell’Angelica, Shotelersuk, Aguilar, Gahl, & Bonifacino, 1999; Huizing
et al., 2002; Jung et al., 2006). Deficiency of this subunit results in dimin-
ished protein stability of the other complex subunits. Loss of the AP-3 com-
plex causes enlargement of lytic granules in CD8+ T cells and their inability
to move along microtubules to coalesce at the microtubule organizing
center (MTOC) prior to MTOC polarization (Clark et al., 2003). This step
152 William A. Comrie and Michael J. Lenardo
3.9.3 LRBA
An autosomal recessive disorder caused by LOF mutations in the LPS-
responsive beige-like anchor protein (LRBA) leading to complete loss of
protein expression was first identified in a large consanguineous family with
early onset IBD (EO-IBD) and combined immunodeficiency with autoim-
munity (OMIM 614700). Patients with LATAIE (LRBA deficiency with
autoantibodies, Treg defects, autoimmune infiltration, and enteropathy)
disease had various combinations of early onset diarrhea, autoimmune pan-
cytopenia, EBV-associated lymphoproliferation, and vitamin B12 deficiency.
While some patients had low B cell and IgG/IgA levels, this was not consis-
tent across all patients (Alangari et al., 2012). Further characterization of
additional LATAIE patients expanded the clinical phenotype to include
chronic lung infections and bronchiectasis and highlighted the importance
of LRBA for B cell activation and class-switched antibody secretion
(Lopez-Herrera et al., 2012). LRBA deficiency also caused decreased num-
bers of FOXP3+ Tregs that had lower expression of the Treg functional
markers CTLA4/CD25 and impaired inhibitory function. This was associ-
ated with increased memory T cell accumulation (Charbonnier et al.,
2015). Extended analysis of a large cohort of LATAIE patients demonstrated
that most patients develop some combination of immune dysregulation,
lymphadenopathy, infections, and hypogammaglobulinemia with defects in
154 William A. Comrie and Michael J. Lenardo
3.9.4 UNC119
Recently a 32-year-old female was described with an autosomal dominant
disease consisting of shingles, oral hepatic lesions, otitis media, persistent
fungal infections, and pulmonary infections with an idiopathic CD4+
T cell lymphopenia (OMIM 615518). The patient’s disease was associated
with a heterozygous dominant-interfering mutation (G22V) in the unc-
119 homologue A protein (UNC119) (Gorska & Alam, 2012). UNC119
acts as a trafficking chaperone for multiple proteins and is involved in endo-
some recycling through the activation of Rab11 (Jaiswal et al., 2016;
Kobayashi, Kubota, Mori, McLaren, & Inana, 2003; Zhang et al., 2011).
In T cells, UNC119 is recruited to the IS and interacts specifically with
Lck via a proline-rich motif in UNC119 and the SH3 domain of Lck in
an activation-dependent manner. This interaction is critical for TCR stim-
ulation as the UNC119/Lck interaction directly contributes to the activa-
tion of this keystone src kinase during TCR signaling (Gorska, Stafford,
Cen, Sur, & Alam, 2004). UNC119 is also critical for the proper trafficking
of Lck to the IS since Lck will accumulate in Rab11+ endosomes in the
absence of UNC119. This defect is likely due to loss of UNC119-mediated
Rab11 activation and it can be overcome through the expression of consti-
tutively active Rab11 or UNC119 reconstitution (Gorska, Liang, Karim, &
Alam, 2009). The G22V mutation is unable to bind Lck, presumably
because the mutation is directly N-terminal to the polyproline motif
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 155
3.11.1 MAGT1
In 2011, our lab identified hemizygous LOF mutations in the X-linked gene
encoding magnesium transporter 1 (MAGT1) in patients with chronic EBV
infection and lymphoma with reduced naı̈ve T cells, low CD4+ T cell
counts, and defective CTL cytotoxicity accompanied by deficits in NKG2D
glycosylation and expression (X-linked magnesium deficiency with EBV
and neoplasia, XMEN disease, OMIM 300853) (Chaigne-Delalande
et al., 2013; Li et al., 2011). MAGT1-deficient cells have reduced basal intra-
cellular Mg2+ levels and are defective in a TCR-mediated Mg2+ flux. This is
consistent with MAGT1’s described role as a magnesium transporter
(Goytain & Quamme, 2005). The MAGT1 protein regulates T cell activa-
tion at an early stage, specifically at the level of PLCγ phosphorylation and
further downstream processes including p65 nuclear translocation, calcium
flux, and activation marker upregulation. As previously mentioned, defects
in Itk/PLCγ may preferentially lead to susceptibility to EBV infections,
which further implicate this molecular pathway in the pathogenesis of
XMEN disease. Interestingly, Mg2+ supplementation in vitro and in vivo
rescues NKG2D expression, CTL function, and resulted in reduced EBV
viral load, but does not affect early TCR-mediated signaling defects
(Chaigne-Delalande et al., 2013). These results are consistent with MAGT1
regulating both a stable basal and transient TCR-induced pool of free Mg2+,
with the former being important for NKG2D glycosylation/stability
and rescued by Mg2+ supplementation and the latter important for TCR
proximal signaling events and not rescued by Mg2+ supplementation. Inter-
estingly, however, MAGT1 is a homologue of yeast OST3 and, along with a
third homologous protein (TUSC3), performs an accessory function to
STT3B-mediated glycosylation (Cherepanova & Gilmore, 2016; Kelleher
& Gilmore, 2006). Thus, the MAGT1 protein may directly modulate gly-
cosyltransferase activity independently, or in addition to, its role in Mg2+
regulation. This raises the additional question of whether MAGT1 is itself
a magnesium channel or indirectly regulates Mg2+ levels by assisting in
the glycosylation of an as-of-yet unidentified channel. Why exactly
MAGT1 deficiency results in such a narrow clinical phenotype is incom-
pletely understood, though it may be possible that TUSC3, a highly homol-
ogous protein encoded on chromosome 8, can compensate in other tissues
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 157
in XMEN patients, thus confining the disease mainly to specific cells of the
immune system.
3.11.2 PGM3
The conversion of GlcNAc-6-P into GlcNAc-1-P is catalyzed by phospho-
acetylglucosamine mutase (PGM3) and is required for the synthesis of
UDP-GlcNAc, a critical nucleotide sugar donor for multiple glycosylation
pathways. Several studies have identified biallelic LOF mutations in PGM3
in an autosomal recessive PID characterized by recurrent bacterial, fungal,
and viral infections, allergies, and T cell lymphopenia (OMIM 615816)
(Lundin et al., 2015; Sassi et al., 2014; Stray-Pedersen et al., 2014b;
Zhang et al., 2014b). Patients show reduced UDP-GlcNAc and decreased
formation of complex N-glycans. Patient T cells skew toward Th2-type
responses possibly accounting for the increased prevalence of allergies in
patients with PGM3 deficiency. Why PGM3 deficiency causes specific
T cell lymphopenia is incompletely understood, however, it is known that
T cells upregulate UDP-GlcNAc and O-GlcNAcylation by O-GlcNAc
glycosyltransferase (OGT) upon activation (Swamy et al., 2016). Addition-
ally, the deletion of OGT in the thymus results in a strong block in thymic
development while its deletion in ex vivo proliferating T cells resulted in
diminished proliferation due to reduced c-Myc expression. Therefore,
PGM3 deficiency may reduce O-GlcNAcylation due to decreased UDP-
GlcNAc which could inhibit c-Myc in PGM3-deficient patients. Supple-
mentation with exogenous GlcNAc increases intracellular UDP-GlcNAc
levels in PGM3-deficient cells thereby bypassing PGM3 in the catalytic
pathway and rescuing the deficient function in ex vivo cell cultures. Hence,
this may represent a useful therapeutic strategy in PGM3 deficiency (Zhang
et al., 2014b).
3.11.3 EXTL3
Biallelic LOF mutations in exostosin-like glycosyltransferase 3 (EXTL3)
lead to an autosomal recessive disease of skeletal dysplasia and immunode-
ficiency characterized by T cell lymphopenia, expansion of a senescent
CD8+ T cell population, reduced TCR-mediated T cell activation, Omenn
syndrome, eosinophilia, and hyper-IgE (OMIM 617425) (Guo et al., 2017;
Notarangelo, 2017; Oud et al., 2017; Volpi et al., 2017). These defects were
linked to a decreased capacity for HSC differentiation and decreased thymo-
poesis, as well as reduced IL-2-dependent signaling. EXTL3 is an α1,4-N-
acetylglucosaminyltransferase that is involved in heparan sulfate biosynthesis
158 William A. Comrie and Michael J. Lenardo
through glycan chain initiation and elongation. How exactly altered heparin
sulfate composition observed in patient cells may be regulating these various
processes remains to be seen, though it should be noted the HSCT was cura-
tive, marking the affected pathway as a T cell-intrinsic defect. It is possible that
modification of certain signaling proteins by heparin sulfate can modulate their
signaling capacity. Precedence for this idea is demonstrated by the require-
ment of CD47 modification by heparan sulfate for thrombospondin-1 to
inhibit T cell activation (Kaur et al., 2011).
3.12.1 EPG5
Biallelic LOF mutations in the gene encoding Ectopic P-granules autophagy
protein 5 homologue (EPG5) leads to a variable PID characterized by recur-
rent viral, bacterial, and fungal infections, and profound CD4+ T cell
lymphopenia, coupled with multiple syndromic features (slow growth,
microcephaly, cleft palate, and heart defects with corpus callosum agenesis,
cataracts, and cardiomyopathy), termed VICI syndrome (OMIM 242840)
(Byrne et al., 2016; Cullup et al., 2013; Ehmke et al., 2014). EPG5 defi-
ciency causes the accumulation of impaired autolysosomes due to defects
in the final maturation step of autophagosomes to autolysosomes necessary
for cargo degradation (Tian et al., 2010). While variable immunodeficiency
has been associated with VICI syndrome, it is not known if EPG5 regulates
T cell memory formation or maintenance and if this is an important aspect of
the immunodeficiency. Interestingly, patient fibroblasts show altered Akt/
mTOR signaling, but this has not been evaluated in patient T cells where
the mTOR pathway is critical for T cell effector responses. Further inves-
tigation into the PID associated with VICI syndrome would be necessary to
understand EPG5’s role in T cell development, effector responses, and
memory formation.
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 159
3.12.2 TPPII
During turnover in both the proteasome and the lysosome/autophagosome,
proteins are first cleaved into long oligopeptides with subsequent processing
by N-terminal tripeptide cleavage by tripeptidyl peptidases (Tomkinson,
1999). Biallelic LOF mutations in tripeptidyl peptidase II (TPPII) results
in a recessive disease of immunodeficiency, autoimmunity, and develop-
mental delay termed “TPPII-related immunodeficiency, autoimmunity,
and neurodevelopmental delay with impaired glycolysis and lysosomal
expansion” (TRIANGLE disease) (OMIM 190470). Patients develop
recurrent viral and bacterial infections, cytopenias, lupus-like disease in
the central nervous system, early-onset Evan’s syndrome, and autoimmune
hepatitis (Lu et al., 2014). Patient CD8+ T cells largely expressed a senes-
cent phenotype with poor proliferative responses (Stepensky et al., 2015).
TPPII was observed to be essential for protein turnover and regulation of
free amino acid levels as well as maintenance of baseline mTOR signaling.
Interestingly, TPPII deficiency/inhibition resulted in increased lysosome
biogenesis and modestly increased autophagosome formation in an appar-
ent compensation for the deficiency in free amino acids. In turn, this leads
to a secondary proteolytic loss of hexokinase 2 and decreased glycolysis/
effector function in TPPII-deficient/inhibited cells. Why TPPII deficiency
results in autoimmunity and a population of activated senescent CD8+
T cells, especially given reduced mTOR activation in TPPII-deficient cells,
requires further investigation. Whether or not TPPII is important for mem-
ory formation or viral control in chronic infection remains to be elucidated,
as does the exact role of autophagy and protein turnover in these processes.
3.13.1 CTPS1
Cytidine 50 triphosphate synthase 1 (CTPS1) is critical for the formation of
CTP, a precursor of DNA, RNA, and phospholipids (Kursula et al., 2006).
160 William A. Comrie and Michael J. Lenardo
While this protein’s function is obvious, it did not have a selective function
in the immune system until WES sequencing identified biallelic LOF muta-
tions in CTPS1 as the cause of an autosomal recessive immunological
disorder (OMIM 615897) (Martin et al., 2014). Patients presented with
recurrent viral and bacterial infections, including severe EBV infection.
Infectious susceptibility was traced to a T cell-specific lymphopenia, with
specific loss of naı̈ve T cells, increased memory T cells, and complete
absence of invariant T cell populations. Interestingly, CTPS1 expression
is low in all cell types, but is specifically and massively upregulated in
antigen-stimulated T cells within days after activation. This implies that
it is a special prerequisite during this period of rapid cell growth and divi-
sion. T and B cell proliferation following in vitro antigen stimulation was
markedly decreased in the absence of CTPS1. Critically, supplementation
of T cells with CTP or cytidine rescued the T cell proliferation defect, sug-
gesting this disorder could be circumvented by providing exogenous end
products of CTPS1 function (Martin et al., 2014). As the plasma membrane
is generally impermeable to nucleoside triphosphates, the use of concentra-
tive or equilibrative nucleoside transporters is required for the uptake of
these biomolecules. Interestingly, several of these transporters are regulated
during immune cell activation and may ultimately prove to be the source of
as-of-yet undefined PIDs (Pastor-Anglada et al., 2001).
3.13.2 AK2
Adenylate kinase 2 (AK2) catalyzes the conversion of ADP to ATP and
AMP, and is thus crucial for the de novo biogenesis of AMP (Noma,
2005). Biallelic LOF mutations in AK2 causes reticular dysgenesis, a severe
SCID phenotype with absence of granulocytes, severe lymphocyte defi-
ciency, hypoplasia of the thymus and lymph nodes caused by an early arrest
in myeloid lineage development and lymphoid maturation with loss of
almost all major immune cellular subsets (OMIM 267500) (Lagresle-
Peyrou et al., 2009; Pannicke et al., 2009). This was traced back to an
increase in spontaneous apoptosis related to defects in mitochondrial func-
tion, oxidative phosphorylation, and ROS production due to altered
homeostasis of ADP, ATP, and AMP (Six et al., 2015).
3.13.3 ADA
Adenosine deaminase (ADA) catalyzes the irreversible deamination of aden-
osine and deoxyadenosine in the purine catabolic pathway. ADA deficiency,
which causes an accumulation of dATP, was first recognized to cause a
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 161
3.13.4 PNP
Biallelic LOF mutations in purine nucleoside phosphorylase (PNP) cause an
autosomal recessive SCID phenotype with frequent bacterial and viral infec-
tions, lymphopenia, a small or absent thymus, and decreased T cell prolif-
eration and function, often accompanied by autoimmune disease (OMIM
613179) (Edwards, Hopkinson, & Harris, 1971; Markert, 1991). PNP cat-
alyzes inosine to hypoxanthine and guanosine to guanine, which ultimately
get degraded to uric acid. In the absence of PNP, there is a build-up of
deoxy-GTP which proves highly toxic to T cell populations, thus leading
to the T cell-specific deficiency.
3.13.5 MTHFD1
Biallelic LOF variants in methylenetetrahydrofolate dehydrogenase,
cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1) result
in an autosomal recessive PID characterized by recurrent lung infections,
moniliasis, liver fibrosis, septic arthritis, multiple cytopenias, and low T,
B, and NK cells, which are sometimes accompanied by autoimmunity
(OMIM 617780) (Burda et al., 2015; Keller et al., 2013; Watkins et al.,
2011). MTHFD1 is an enzyme that catalyzes three separate steps in folate
metabolism by processing single carbon folate derivatives utilizing three sep-
arate protein domains (Hum, Bell, Rozen, & MacKenzie, 1988). Vitamin
B12 and folate replacement in MTHFD1-deficient patients resulted in
reconstitution of T and B cell counts, and rescued response to mitogenic
stimuli. Thus, in metabolic disorders, such as MTHFD1 deficiency, supple-
mentation of patients with end products of the pathway can overcome the
endogenous deficiency in metabolite synthesis, though this likely depends
on metabolite bioavailability.
162 William A. Comrie and Michael J. Lenardo
3.13.6 TFRC
Biallelic LOF mutations in the transferrin receptor (TFRC), which is critical
for iron uptake, results in an autosomal recessive PID characterized by mild
anemia, intermittent neutropenia, and defective B and T cell activation and
memory formation, despite normal lymphocyte counts (OMIM 616740)
(Jabara et al., 2016; Lo, 2016). The identified TFRC mutation results in
overall increased TFRC protein production and cell surface expression
and, concomitantly, reduces receptor internalization following stimula-
tion. The addition of iron citrate, which saturates the transferrin receptor
and allows iron internalization independent of TFRC rescued T and B cell
proliferation and class switching defects. This study illustrates how the
molecular investigation of PIDs reveals previously unknown roles of
known proteins in immune function, as this was the first appreciated role
of TFRC in host defense. While TFRC deficiency is the first known PID
associated with cell-intrinsic iron uptake, it has long been known that iron
deficiency results in poor T and B cell responses and decreased cellularity
(Bowlus, 2003).
3.14.2 CD55
The significance of complement signaling in the function of human T cells
was demonstrated by Ozen et al. who recently described CD55 deficiency
with hyperactivation of complement, angiopathic thrombosis, and protein-
losing enteropathy (the CHAPLE syndrome) (Ozen et al., 2017). The
CD55-deficient patients also exhibited T cell-intrinsic defects in IL-10 pro-
duction and enhanced TNF production (OMIM 226300) (Ozen et al.,
2017). CD55 is a cell surface complement inhibitory protein that is
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 163
3.15.1 SP110
Biallelic LOF mutations in SP110 nuclear body protein (SP110) cause an
autosomal recessive disorder with veno-occlusive disease and immunodefi-
ciency characterized by infection susceptibility, low T cell numbers, hyp-
ogammaglobulinemia, and decreased germinal center and plasma cell
formation (OMIM 235550) (Roscioli et al., 2006; Wang, Ong, Roscioli,
Cliffe, & Church, 2012). In its best known function, SP110 associates with
the nuclear body and may either act as a nuclear hormone receptor or as an
activator of NF-κB under certain circumstances, though neither role has
been well validated (Bloch et al., 2000; Leu et al., 2017).
3.15.2 TTC7A
Biallelic mutations in tetratricopeptide repeat domain 7A (TTC7A) cause an
autosomal recessive combined syndrome of immunodeficiency, autoimmu-
nity, and intrinsic GI defects (OMIM 243150) (Chen et al., 2013). These
patients have reduced B and T cell populations with poor antibody produc-
tion and T cell proliferation to mitogen. Patient intestinal organoids showed
defects in polarity formation with increased activation of RhoA targets—
pERM and phosphorylated myosin light chain. Rho-associated protein
kinase (ROCK) inhibition resulted in reversion of polarity, suggesting
164 William A. Comrie and Michael J. Lenardo
increased RhoA signaling may be the cause of patient disease (Bigorgne et al.,
2014). Patient PBMCs also have increased spontaneous phosphorylation of
ERM proteins and MLC, with increased TCR- or integrin-mediated
T cell spreading. Additionally, patient cells express decreased chemokine
receptors and migrated poorly compared to control cells. Finally, patient
T cells were hyperproliferative, which could be corrected by ROCK inhi-
bition (Lemoine et al., 2014). In a known function, TTC7A regulates PI4KA
localization, with TTC7A knockdown resulting in poor PIP production and
mutant TTC7A associating poorly with PI4KA (Avitzur et al., 2014). Despite
these strong hints, the precise effect of TTC7A on RhoA and PI4KA func-
tion, and if these represent separate or linked biochemical functions of
TTC7A, are undetermined.
sequencing (Belkadi et al., 2015). The tradeoff for the better sequence data is
the time and cost associated with whole-genome sequencing and the diffi-
culty inherent in analyzing noncoding variants—both problems that will
diminish with time.
Once a list of rare genetic variants that track with disease has been devel-
oped, there are usually multiple candidate variants remaining, especially
when only a single affected individual is available for analysis. Prioritization
of these candidate variants then occurs based on algorithms that predict a
deleterious effect on protein function (PolyPhen/CADD, etc.), the
observed vs expected mutation rates in the gene encoding the protein in
large-scale genetic databases such as ExAC, the tissue expression pattern
of the protein, the known or hypothetical roles of the protein, and the avail-
ability of genetic models in animals including mice, zebrafish, flies, etc. All of
this information is subjectively analyzed and variants are ranked for follow-
up analysis. Importantly, while coding variants (missense, nonsense, and
splice site) are perhaps the easiest to identify and study, noncoding variants
(promotor/enhancer/silencer mutations, copy number variation, intronic,
and synonymous) must also be considered as these can affect transcription,
translation, mRNA stability, or splicing of the affected gene, all with impacts
on protein function. Another interesting way to prioritize candidate genes is
the identification of genes likely to cause human disease based on their rela-
tionship with previously identified human PID genes. This approach has
shown good predictive capacity in identifying genes associated with yet-
undiscovered PIDs (Itan & Casanova, 2015).
Perhaps the easiest way to strengthen the argument that mutations in a
given gene are the cause of disease is the identification of multiple individuals
with a similar clinical phenotype with highly deleterious variants in the same
gene. Still, this does not move past correlation to implicate causation. To
move in this direction, additional laboratory testing must be done to estab-
lish that the given variant is deleterious to protein function and affects the
biological pathway that is presumed to be associated with disease. Usually
this first entails the identification of an in vitro cellular phenotype associated
with disease followed by add back of WT protein to patient cells or intro-
duction of patient protein/knockout of the gene in WT cells to determine if
these correct or phenocopy patient cellular defects, respectively. This can be
supplemented with pharmacological inhibition of the affected biochemical
pathway and the generation/use of genetically engineered animal models.
Casanova et al. have established three general guidelines that should be
viewed as prerequisites to identification and publication of causal genes in
166 William A. Comrie and Michael J. Lenardo
cases involving a single affected individual (Itan & Casanova, 2015). First,
family and population genetics should indicate that the candidate genotype
is monogenic and the potential causal variant does not occur in healthy indi-
viduals. Second, experimental and mechanistic studies must prove that the
candidate variant is deleterious to the expression or function of the protein
product. Finally, the connection of the candidate gene and patient pheno-
type must be established by known molecular interactions, expression patterns,
and a relevant cellular or animal phenotype. Stated differently, the variant must
be proven deleterious and absent from healthy individuals and the gene the
variant resides in must be plausibly important for the disease mechanism. In
cases where a single patient has already been published, follow-up reports
are useful confirmations of gene–disease relationships and often provide insight
into the clinical spectrum of disease. Hence, although specific gene implication
will always involve a measure of correlation, if that can be established at the
molecular, cellular, and organismal levels, the hypothesis of causality is substan-
tially strengthened.
As mentioned throughout this review, identification of the causal variant
can lead to targeted therapeutic interventions. This has proven to be one of
the most exciting and gratifying aspects of genomic research. Those working
in the field of PID research and immunology is especially fortunate since
their “organ” of interest can be replaced through bone marrow transplanta-
tion. This enables a measure of manipulability that is unparalleled in other
organs in the body. The development of new treatments or the deployment
of known, but perhaps unobvious, treatments are facilitated by strong mech-
anistic evidence identifying the affected biochemical pathway in patient cells
and the availability of interventions that can target this pathway. In many
cases where disease is confined to the immune system and there is no known
targeted therapeutic option, HSCT is indicated as the principle course of
action. However, disease must be severe enough to warrant the inherent risk
associated with HSCT. More recently, the treatment of several PIDs
by genetic therapy based upon viral restitution of the gene/protein encoded
by the affected genetic loci, has been successful (Mukherjee & Thrasher,
2013). In the future, gene editing by CRISPR/Cas9 and similar technolo-
gies will likely play an important role in correcting these monogenic disor-
ders. Both gene therapy and genetic editing are made more attractive
in PIDs than other primary genetic disorders because it is possible to virtually
replace the all or part of the immune system with corrected material through
radioablation and replacement of patient bone marrow, or simple trans-
fer of corrected HSCs allowing for the outgrowth of corrected cells.
Molecular Classification of Primary Immunodeficiencies of T Lymphocytes 167
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