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Effector mechanisms of

immunity
Jan eromski
2012/2013

Nobel 2011 in physiology and medicine


devoted to key findings in immunology

prof. Bruce Beutler


(USA)

prof. Jules A.
Hoffmann
(France)

They determined conditions of activation of


nonspecific (innate) immunity and detected close
links between the induction of infection and the
reactivity of Toll-like receptors at molecular level

prof. Ralph Steinmann


(USA)

Detected dendritic cells and


determined their function as
antigen presenting cells (APC).

POINTS TO BE DISCUSSED

Cytokines, their receptors and effector function


Macrophages
Granulocyte effector functions
Cytotoxic T cell function
Natural killer cells and natural killer T cells
Effector action of antibodies
Antibody dependent cell mediated cytotoxicity
(ADCC)
Complement functions

GENERAL PROPERTIES OF
CYTOKINES (CT)
Production induced by: a) microbial products in
innate immunity, b) foreign antigens in acquired
immunity, c) own metabolites
Short secretion transient and unstable activation
of transcription
Lack of stability of mRNA
Pleiotropic action on various cells, organs and
systems

THREE FORMS OF IL-2 RECEPTOR

INHIBITION OF CYTOKINE ACTION

CELLS WITH CYTOTOXIC POTENTIAL

ROUTES OF
CYTOTOXICITY

FUNCTIONAL STAGES OF MACROPHAGES

ANGRY
MACROPHAGE

FEATURES OF ACTIVATED
MACROPHAGES
Increased expression of MHC molecules
Increased expression of costimulators (B7-1 and B72, CD40)
Secretion of cytokines (TNF, IL-1, IL-12, IL-18,
IFN, PDGF)
Secretion of chemokines
Expression of enzymes catalysing the production of
microbicidal substances in phagolysosomes (ROI,
nitric oxide, proteolytic enzymes)

POTENTIAL MECHANISMS OF
CYTOTOXICITY OF MYELOID CELLS

Cationic proteins (defensins): small peptides,


comprise up to 50% of the granule proteins.
Form ion-permeable channels in lipid bilayers
of bacteria

Lysozyme, C3a

BPI (bactericidal/permeability increasing factor)

POTENTIAL MECHANISMS OF
CYTOTOXICITY OF MYELOID CELLS-2

Hydrolases

Reactive oxygen intermediates (ROIs)

NO and reactive nitrogen intermediates


(RNI)

Tumor necrosis factor-alpha (TNF-alpha)

NET-osis novel mechanism of killing


bacteria by neutrophils
Neutrophils form network-like structures, consisting of
nucleic acids, histones and enzymes,
These nets have the ability of
immobilizing and killing pathogens
Neutrophils released from the net undergo apoptosis
Net may be formed only by fully mature and intact cells

MAIN CYTOTOXIC AGENTS OF


LYMPHOCYTES

Perforin, granzymes (fragmentins)


(induction of apoptosis)
Lysosomal enzymes (proteolysis, induction
of apoptosis)
Granulolysin (lipid binding protein,
membrane damage)
Fas - FasL (induction of apoptosis)

MAIN CYTOTOXIC AGENTS OF


LYMPHOCYTES - 2

TNF (tumor necrosis factor)


LT-alpha (lymphotoxin alpha)
TRAIL (TNF-related apoptosis inducing
ligand)
Leukoregulin (sensitizer for cytotoxic
action)
ATP, ROI, RNI (increased membrane
permeability)

CYTOTOXIC FACTORS OF LYMPHOCYTE


GRANULES

Granzymes (fragmentins) serine


proteases.Penetrate cell through perforin
channels. Induce apoptosis. Hydrolize
extracellular matrix components
Granulolysin belongs to saponins, lipid
binding proteins. Destroys cell and
mitochondrial membranes.

CTL EFFECTOR FUNCTIONS


1. Cytotoxicity
Granule exocytosis pathway (perforin, granzymes)
Fas /FasL pathway, TNF/TNF-R (?)

2. Inflammation and immunity

Cytokine and chemokine production (IFN-,


TNF-, MIP1, MIP1, RANTES)
Macrophage activation
Direct antiviral effects

CYTOTOXIC FACTORS OF LYMPHOCYTE


GRANULES

Cytolytic granules are the product of Golgi


apparatus
Perforin glycoprotein (555 aminoacids),
similar to C6-C9 complement components,
Ca ions dependent; its polymerization leads
to formation of channels in cell membrane

GRANULE ASSOCIATED KILLING MECHANISMS

RECEPTOR MEDIATED KILLING


MECHANISMS

CYTOTOXIC T LYMPHOCYTES (1):


Provide partial protection from:
Most viruses
Some bacteria (e.g. Listeria monocytogenes,
Mycobacterium tuberculosis)
Some protozoa (e.g. Trypanosoma cruzi,
Toxoplasma gondi, Plasmodium falciparum
Tumors

CYTOTOXIC T LYMPHOCYTES (2):

Contribute to or cause:
1. Hypersensitivity reactions such as
tissue damage in several infectious
diseases,
2. Some autoimmune diseases,
3. Organ transplant rejection,
4. Graft-vs-host disease.

OVERVIEW OF LYMPHOCYTE
RESPONSES

FEATURES OF NK CELLS
Granular lymphocytes, express CD16 and
CD56, but NOT CD3
Spontaneously cytotoxic to certain tumors
and virally infected cells
Found in the blood, spleen, lung, liver, GI
tract and uterine decidua
Activated by IL-2, IL-12, IL-15 or IL-18

FEATURES OF NK CELLS -2
Subsets express killer immunoglobulin-like
receptors (KIR) for class I MHC antigens.
Long ones possess ITIM (immunoreceptor
tyrosine based inhibitory motif) domain
(inhibitory), while short ones have ITAM
domain providing activatory (death) signal
Target cell lysis via perforin/granzymes
pathways and receptor induced apoptosis

Mechanisms of NK cell cytotoxicity


Release of cytokines (IFN gamma, TNF and
others)
Release of cytolytic granules for lysis of
infected or transformed cells
Induction of target cell death through cell
surface receptors

RECEPTORS AND LIGANDS OF


NK CELLS
Receptors
immunoglobulin-like
receptors
C-type lectins - CD94NKG2A-F in man
Natural cytototoxicity
receptors

Ligands
Class I HLA-C alleles

HLA-E with HLA-A:C leader


peptide

Influenza hemaglutinin, C-type


lectin

CYTOTOXICITY OF NK CELLS

NKT (CD3+, CD56+) cells


Recognize antigens in the context of CD1d (one of five
nonpolymorphic MHC class I glycoproteins (CD1a-e),
CD1d molecules present nonprotein and glycolipid antigens
(components of mycobacterial walls)
NKT cells are few in the blood (0,3%) but abundant in liver
(4% of all lymphocytes)
They secrete IFN-, TNF, but may also IL-4, IL-10,IL-13
Cytotoxicity CD1d restricted, either Fas mediated or perforin
dependent

EFFECTOR FUNCTIONS
OF ANTIBODIES
Neutralization of microbes (bacteria and viruses)
Inactivation of toxins
Opsonization of microbes with subsequent
phagocytosis
Antibody dependent cellular cytotoxicity (ADCC)
Activation of classical pathway of complement
(IgG, IgM)
Mast cell and basophil degranulation (IgE)

CLASS SWITCHING AND AFFINITY


MATURATION ENHANCE THE PROTECTIVE
FUNCTIONS OF ANTIBODIES
Heavy chain class switching cf. From IgM to
IgG or IgA results in production of antibodies
with distinct Fc regions, ready to perform various
effector functions,
Affinity maturation prolonged antigen
stimulation leads the production of antibodies with
higher and higher affinities for the antigen. This
results in increased ability of antibodies to
neutralize or eliminate microbes,
Avidity the sum of affinity receptors

ANTIBODY DEPENDENT CELLMEDIATED CYTOTOXICITY (ADCC)


Is due to Fc receptor for IgG (CD16) on effector cell
Fc receptor on effector cell binds Fc fragment of
antibody bound to target cell, what enables direct
contact between effector and its target
Cells possessing Fc receptor are called killer cells (Kcells).They include NK cells, T cells, monocytes,
eosinophils, some other myeloid cells (polymorphs?)

CYTOTOXICITY of COMPLEMENT

THANK YOU!

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