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HOW THE IMMUNE
SYSTEM WORKS
Václav Hořejší
Inst. of Molecular Genetics AS CR,
Prague, Czech Republic
BASIC TASKS:
- PROTECTION FROM PATHOGENS
- REMOVAL OF ABNORMAL SELF CELLS
RECOGNITION
RECOGNITION OF PATHOGENS
AND ABNORMAL SELF CELLS
BY MEANS OF:
- SURFACE RECEPTORS
- “SOLUBLE RECEPTORS”
INNATE (NON-ADAPTIVE)
SYSTEM
SOLUBLE AND MEMBRANE RECEPTORS OF
THE INNATE SYSTEM (MAINLY ON VARIOUS
TYPES OF PHAGOCYTES) RECOGNIZE:
PATHOGEN-ASSOCIATED MOLECULAR
PATTERNS (PAMPs)
The number of the innate receptors is limited,
shared structural features are recognized
MANNOSE-BINDING LECTIN,
COMPLEMENT
TOLL-LIKE RECEPTORS
SURFACE LECTINS
A SPECIAL SORT OF THE CELLS OF THE
INNATE (NON-ADAPTIVE) SYSTEM ARE
NK (NATURAL KILLER) CELLS.
SPECIALIZE IN KILLING OF ABNORMAL
SELF CELLS CONSPICUOUS BY LOW
EXPRESSION OF MHC MOLECULES (e.g.
many tumors).
ADAPTIVE
(ANTIGEN-SPECIFIC)
SYSTEM
THE ADAPTIVE SYSTEM:
- Based on huge repertoir of B- and T-lymphocyte
clones, each carrying a slightly different receptor
(BCR or TCR)
- The “soluble receptors” of the adaptive system are
antibodies (= soluble BCR)
- The system is “anticipating”, clonal, “wasteful”
- Clonal receptors arise mainly by gene
rearrangement and somatic mutations.
B CELL DIFFERENTIATION
T LYMPHOCYTE DEVELOPMENT
AND SELECTION IN THYMUS
T-CELL RECEPTORS:
MAINLY RECOGNITION OF MHC-PEPTIDE
COMPLEXES ON OTHER CELL’S SURFACE
PURPOSE: DETECTION OF CELLS
INFECTED BY “HIDDEN” INTRACELLULAR
PARASITES (e.g. VIRUSES)
PRODUCTIVE STIMULATION OF T LYMPHOCYTES
REQUIRES PROFESSIONAL APC (DC) AND COSTIMULATION
T LYMPHOCYTES:
IMPORTANT FUNCTIONAL SUBSETS
Leo A., Schraven B.Curr Opin Immunol 2001 Jun;13(3):307-16
BASIC DOGMA FOR THE
ADAPTIVE RESPONSES:
ANTIBODY RESPONSES (B, Th2) – EFFECTIVE FOR
EXTRACELLULAR PARASITES
INFLAMMATORY RESPONSES (Th1, Tc) – EFFECTIVE FOR
INTRACELLULAR PARASITES
MUTUAL INHIBITION Th1 vs. Th2 (POSITIVE FEEDBACK
REGULATION)
WRONG CHOICE Th1 vs. Th2 CAN BE FATAL (LEPROSY…)
Th1 x Th2
ESSENTIAL LINK BETWEEN THE
INNATE AND ADAPTIVE SYSTEMS:
DENDRITIC CELLS
DENDRITIC CELLS MUST BE
PRE-STIMULATED BY
DANGER SIGNALS
TO BE ABLE TO ACTIVATE
T LYMPHOCYTES
DANGER SIGNALS:
- EXOGENOUS (PAMPs)
- ENDOGENOUS (e.g. STRESS PROTEINS
RELEASED FROM NECROTIC CELLS)
DISPOSAL
EFFECTOR MECHANISMS OF
PATHOGEN REMOVAL
(FOLLOWING RECOGNITION BY EITHER INNATE OR
ADAPTIVE RECEPTORS):
- KILLING BY MIROBICIDAL PEPTIDES, REACTIVE OXYGEN
SPECIES, OR OTHER “CHEMICAL WEAPONS”
- PHAGOCYTOSIS
- INFLAMMATION (BASED ON CYTOKINES, CHEMOKINES)
- KILLING (NOT CURING!!) OF INFECTED CELLS
PHAGOCYTOSIS
SELF-TOLERANCE
BIG PROBLEM:
HOW TO MAINTAIN SELFTOLERANCE AND PREVENT
AUTOIMMUNITY?
IMMUNOLOGICAL HIT
(WITH EMBARRASSING HISTORY…)
REGULATORY (= SUPPRESSOR) T
LYMPHOCYTES
(Treg, Ts, Th3, Tr1…)
REGULATORY T LYMPHOCYTES ARISE IN:
- THYMUS (SUPPRESS AUTOIMMUNITY)
- PERIPHERY (THESE DOWN-REGULATE
EXCESSIVE IMMUNE RESPONSES
PRACTICAL
CONSEQUENCES?
HOPEFULLY:
- BETTER VACCINES (WEAK ANTIGENS,
TUMORS?)
- IMMUNOSUPPRESSION (AUTOIMMUNE
DISEASES, TRANSPLANTATION)
CENTURY – THE AGE OF
IMMUNOTHERAPEUTICS?
st
21
WE WILL SEE IN 20, 50, 100 YEARS…
SUMMARY:
- RECOGNITION BY SOLUBLE OR MEMBRANE-ASSOCIATED RECEPTORS
- INNATE SYSTEM (LIMITED NUMBER OF PAMP-RECEPTORS)
- ADAPTIVE SYSTEM (HUGE REPERTOIR OF HIGHLY SPECIFIC CLONAL
RECEPTORS)
- CRUCIAL ROLE OF DENDRITIC CELLS IN LINKING OF THE INNATE
AND ADAPTIVE SYSTEM
- DANGER SIGNALS (EXOGENOUS OR ENDOGENOUS) “WAKE UP” DC’s
FOR STIMULATION OF T CELLS
- CRUCIAL ROLE OF THE DECISSION FOR THE ANTIBODY-BASED (Th2)
vs. INFLAMMATORY (Th1, Tc) RESPONSES
- CRUCIAL ROLE OF SELF-TOLERANCE MECHANISMS (DELETION OF
AUTOREACTIVE LYMPHOCYTES, REGULATORY T CELLS)
MOLECULAR MECHANISMS:
THOUSANDS OF MOLECULES,
RECEPTORS, CYTOKINES,
PATHWAYS…
Leo A., Schraven B.Curr Opin Immunol 2001 Jun;13(3):307-16
LIPID RAFTS (GEMs)
TM protein
TM protein
CD48
TM protein
CD55
CD59
GLP
LAT
Lck
Fyn
RAFTs - DISTRIBUTION AND HETEROGENEITY
GEMs IN IMMUNORECEPTOR SIGNALLING
MHC
GPI-domain
TCR complex
CD4/8
CD48
MHC
TCR
CD55
CD59
CD3
GLP
LAT
Lck
Fyn
CD3
()2
1
5
1
3
4
2
ZAP-70
TRANSMEMBRANE ADAPTOR PROTEINS
(TRAPs) IN GENERAL
Closely associated with
immunoreceptors
Not associated
with rafts
Associated with rafts
(palmitoylated)
Signaling components of leukocyte rafts:
Src kinases:
Štefanová et al, Science 254(1991)1016
Cinek et al, J. Immunol. 149(1992)2269
Transmembrane adaptor LAT (critical for TCR signaling):
Brdička et al, Biochem. Biophys. Res. Commun. 248(1998)356
Transmembrane adaptor PAG (activates Csk – regulation of Src-kinases):
Brdička et al, J. Exp. Med. 191(2000)1591
Transmembrane adaptor NTAL (LAT-like function in BCR and FcR signaling):
Brdička et al, J. Exp. Med. 196(2002)1617
Transmembrane adaptor p33 (a role in CD4, CD8 signaling?):
Brdičková et al, submitted
Collaboration with Burkhart Schraven (Heidelberg, Magdeburg)