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 SELF- TOLERANCE 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)

21 st CENTURY – THE AGE OF IMMUNOTHERAPEUTICS? 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)

RAFTs - DISTRIBUTION AND HETEROGENEITY

GEMs IN IMMUNORECEPTOR SIGNALLING

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)