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Cell-mediated cytotoxicity
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10 Immunology
CELL-MEDIATED CYTOTOXICITY
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Immunology 10
NATURAL KILLER CELL RECEPTORS
Fig. 10.4 Leader peptides from MHC class I molecules are loaded
onto HLA-E molecules in the endoplasmic reticulum, a process
which requires TAP transporters and tapasin to assemble
functional HLA-E molecules. These are presented at the cell
surface for review by the CD94 series of receptors on NK cells
(left). The MHC class I molecules meanwhile present antigenic
peptides from cytoplasmic proteins which have been transported
into the endoplasmic reticulum. These complexes are presented
to the TCR on CD8+ cytotoxic T cells.
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CELL-MEDIATED CYTOTOXICITY
An intriguing recent discovery is that the HLA-G molecule, which is expressed only on placental trophoblasts,
is a dominant NK-cell inhibitor that confers resistance to
all types of NK cells (HLA-G is another MHC class 1b
molecule). Trophoblast cells are derived from the fetus
and invade the maternal circulation as the placenta is
established. They are therefore allogeneic in the mother,
because they contain paternal MHC genes. However,
all conventional MHC genes are downregulated in these
cells, and the HLA-G expression is therefore required to
protect the placenta from attack by NK cells. There is some
debate as to which of the inhibitory receptors recognize
HLA-G. Both CD94 and several of the better-defined
KIRs have been excluded, but a likely candidate is ILT2.
The next question is how a NK cell decides between cytotoxic action or inaction. This decision is thought to depend
on the coordination of intracellular signalling pathways,
and may involve the balance between activating and
inhibitory signals. Both the lectin-like receptor and the
KIRs occur as inhibitory or activating molecules. The
key difference is the presence of immunoreceptor tyrosine
inhibitory motifs or ITIMs. If these motifs become
phosphorylated, they can recruit phosphatases which
downregulate the activity of the NK cell (Fig. 10.7).
By contrast, other KIRs which lack the ITIMs can associate with a molecule (DAP12) which is related to the
chain of the T-cell receptor complex. This molecule has
immunoreceptor tyrosine activation motifs (ITAMs),
which allow it to phosphorylate and recruit tyrosine kinases
including ZAP-70 (Fig. 10.7, and compare with figure 6.21),
which lead to cell activation. At present, it is not known
how the balance of activation and inhibition is resolved. In
particular it is uncertain how a ligand such as HLA-C will
act when it can bind to both inhibitory and activating
receptors on the same cell.
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MECHANISMS OF CYTOTOXICITY
MECHANISMS OF CYTOTOXICITY
Cytotoxicity is effected by direct cellular
interactions, cytokines and granule exocytosis
Cytotoxic T cells, NK cells and K cells use a variety of
different mechanisms to kill their targets. These include
direct cellcell signalling via surface molecules and indirect
signalling via cytokines. In addition, many CD8+ cytotoxic
T cells and large granular lymphocytes (NK cells and K
cells) have granules which contain proteins that damage
target cells if they are released directly against the target
cell plasma membrane. Exactly which combination of these
three mechanisms is used depends on the Tc cell involved.
F i g .1 0 . 8 The molecule Fas (CD95), the two TNF receptors and the
lymphotoxin receptor are illustrated diagramatically. The extracellular domains are similar to those found in the NGF receptor.
Both Fas and TNFR-1 have death domains which are involved in
the recruitment of caspases. The ligands for these receptors are
indicated at the top. Lymphotoxin- can form homotrimers or
heterotrimers with lymphotoxin-. Up to 25 other members of
these families have been identified by data-base searching.
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CELL-MEDIATED CYTOTOXICITY
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NON-LYMPHOID CYTOTOXIC EFFECTORS
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CELL-MEDIATED CYTOTOXICITY
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NON-LYMPHOID CYTOTOXIC EFFECTORS
CRITICAL THINKING
number of ways. Binding to IgG-coated parasites via surface Fc RII triggers release of some mediators including
ECP, but not EPO. By contrast, triggering via FcRII leads
to the release of EPO, but not ECP. Parasite killing may
involve contact-dependent degranulation or may simply
require deposition of toxins within the local tissue. Degranulation may also be triggered directly in vitro by several
cytokines, including IL-3, IL-5, granulocyte-macrophage
colony-stimulating factor (GM-CSF), TNF, interferon-
(IFN) and platelet activating factor (PAF). These mediators
also enhance ADCC-mediated degranulation. Eosinophils
are prominent in the inflammatory lesion of a number of
diseases, particularly atopic disorders of the gut, skin and
respiratory tract, where they are often closely associated
with fibrotic reactions. Examples are atopic exzema, asthma
and inflammatory bowel disease. Although eosinophils
may play some regulatory role in these conditions, such as
inactivating histamine, their toxic products and cytotoxic
mechanisms are a major cause of the tissue damage. For
example, in asthma, eosinophil granule proteins are detectable in the blood and lungs following asthmatic attacks.
MBP can kill some pneumocytes and tracheal epithelial
cells while EPO kills type II pneumocytes. MBP can also
induce mast cells to secrete histamine, thus exacerbating
allergic inflammation.
Mechanisms of cytotoxicity
Lysis
DNA fragmentation
4%
1%
CD8 Tc cells
82%
80%
NK cells
12%
11%
5%
1%
28%
28%
Purified perforin
95%
2%
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CELL-MEDIATED CYTOTOXICITY
FURTHER READING
Berke G. The binding and lysis of target cells by cytotoxic lymphocytes.
Annu Rev Immunol 1994;12:735.
Bleackle RC, Lobe CG, Duggan B, et al. The isolation of a family of
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Boyington JC, Motyka SA, Schuck P, Brooks AG, Sun PD. Crystal
structure of an NK cell immunoglobulin-like receptor in complex with
it class I MHC ligand. Nature 2000;405:53743.
Kagi D, Ledermann B, Burki K, et al. Cytotoxicity mediated by T cells and
natural killer cells is greatly impaired in perforin-deficient mice.
Nature 1994;369:317.
Lanier LL, Phillips JH. Inhibitory MHC class I receptors on NK cells and T
cells. Immunol Today 1996;17:8691.
Lee N, Llano M, Carreto M, et al. HLA-E is a major ligand for the natural
killer inhitory receptor CD94/NKG2A. Proc Natl Acad Sci
1998;95:5199204.
Lpez-Botet M, Belln T. Natural killer cell activation and inhibition by
receptors for MHC class I. Curr Opin Immunol 1999;11:3017.
Navarro F, Llano M, Belln T, Colona M, Geraghty DE, Lpez-Botet M.
The ILT2 (LIR-1) and CD94NKG2A cell receptors respectively
recognise HLA-G1 and HLA-E molecules on coexpressed targets.
Eur J Immunol 1999;29:27783.
Rathmell JC, Thompson CB. The central effectors of cell death in the
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