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)

21st 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)

Lck

TM protein

CD48CD55

CD59

GLP

Fyn

LAT

TM protein

TM protein

RAFTs - DISTRIBUTION AND HETEROGENEITY

1 1

2

3

4

M H C M H C

Z A P -7 0

G P I-d o m a in T C R co m p lex

L ck

C D 48C D 55

C D 59

G L P

F ynL AT

T C RC D 4/8

C D 3 C D 3

()2

5

GEMs IN IMMUNORECEPTOR SIGNALLING

TRANSMEMBRANE ADAPTOR PROTEINS (TRAPs) IN GENERAL

Closely associated withimmunoreceptors

Not associatedwith rafts

Associated with rafts(palmitoylated)

Signaling components of leukocyte rafts:

Src kinases:Štefanová et al, Science 254(1991)1016Cinek 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)