NEGATIVE REGULATION OF THE IMMUNE SYSTEM

NEGATIVE REGULATION OF THE IMMUNE SYSTEM

NEGATIVE REGULATION IN THE IMMUNE SYSTEM1. Decrease of antigen concentration in the course of the immune response2. Inhibition of B lymphocyte activation - antibody feedback

• Cross linking of BCR with FcRIIB (CD32) by antigen-antibody complex• ITIM-induced negative signaling of B cell activation - phosphatases• B cells without T cell help are excluded from follicles

3. Death of activated T lymphocytes• Passive cell death mediated by the shortage in survival factors (cytokines)• Activation induced FasL expression sensitizes activated T cells for Fas-• mediated apoptosis (AICD)• Activation induced cell death (AICD) is induced by repeated antigenic

stimulation4. Inhibition T lymphocyte activation• Anergy of CD4+ T lymphocytes • Late in the immune response activated T cells express CTLA-4, the ligand of

B74. Suppression by regulatory T lymphocytes

• Counter regulation of Th1 and Th2 cytokines• Production of suppressive cytokines• IL-10 inhibits APC function such as IL-12 secretion and B7 expression• TGF inhibits T-cell proliferation• IL-4 inhibits IFN-mediated functions• IL-10 and TGF inhibit macrophage activation

NEGATIVE REGULATION OF IMMUNE RESPONSES

Days5 10 15 20 25 30

Naive lymphocytes

Number of antigen specific cells

Primary effectors

Secondary effectors

Memory

DIFFERENTIATION

AICD

EXPANSION

AICD

MEMORY

Ia

SS

SS

SS

SS

SS

Ib

SS

SS

IIb1 IIb2/IIb3

S S S SS S

SS

SS

IIIa IIIb

SS

SS

SS

SS

SS

SS

ITIMITAM

S S

IIc

SS

SS

IIa trimerCa2+

Ca2+Ca2+

SS

ITAM

SS

tetramer

-S-S--S-S-

SS

SS

ITAM

SS

SS

SS

SS

SS

SS

poli-Ig receptor

SECRETORY PIECE

ITAM

Iγ-γ

FcγRI (CD64) FcεRIIFcγRII (CD32)

IIIaζ-ζ IIIaζ-γ IIIaγ-γ IIIaβ

α β γ-γ α γ-γ

γ-γ α

FcεRI

FcγRIII (CD16)

IMMUNOGLOBULIN BINDING Fc RECEPTORS

IgG Fc receptors

FcRI

Ig supergene family, MIRR

Activating receptorITAM

Expression Inhibitory receptorITIM

Expression

Fc receptorok

Ig supergene family BCR* B cell

TCR,* CD3* T cell

FcRIa (CD64)FcRI*

Macrophage, DC (internalization)

FcRIIa (CD32) Macrophage, DC (internalization)

FcRIIb (CD32) B cell

FcRIIIa (CD16) FcRI* vagy *

NK cell (ADCC)

FcRI, FcRI* Mast cell (ADCC)

C-type lectin

FcRIIb (CD23b) FcRIIa (CD23a) B cell

MHC I receptorok

Ig supergene family Human KAR Human KIR NK and T cell

C-típusú lektin Egér KIR

Human NKG2C/D NK and regulatory T cell Human NKG2A/B NK and regulatory T cell

Other receptors

BCR CD22 B cell

CD28 CTLA-4 T cell

MIRR Multisubunit Immune Recognition Receptors The ligand binding and signal transducing subunits are separated, they co-localize in membrane microdomains.

ITAM

ITIM

NEGATIVE REGULATION OF B LYMPHOCYTES BY IMMUNE COMPLEXES

FcRIIb

CD28

Activated T cell

CD28 cross linked by B7

Costimulatory molecules also associatewith inhibitory receptors

CTLA-4 binds CD28 with a higher affinity than B7 molecules

/CTLA-4

B7

CD28

T cell

B7

2 2Signal 1 +

Co-stimulationinduces CTLA-4

The lack of signal 2 to the T cell shuts down the T cell response.

Cross-linking of CTLA-4by B7 inhibits co-stimulationand inhibits T cell activation

- - -- -

NEGATIVE REGULATION OF T CELL ACTIVATION BY CTLA-4

CTLA-4

CD28

B7

LATE EXPRESSION

HIGHER AFFINITY TO B7 THAN CD28

TAPC

C D 8 + Tc

F a s

C D 4 + T h 1

F a s L

C D 4 +

T h 1

A P C

B

THE ROLE OF CD4+ T CELLS IN APOPTOSIS

T CELL HOMEOSTASIS SHUT OFF IMMUNE RESPONSES

REGULATORY T CELLS

TregTregCD25IL-2Rα

CTLA4B7 ligand

GITR

MARKERS OF THYMUS DERIVED NATURAL Treg CELLS

CD127IL-7Rα ↓

Treg differentiation, maintenance, functionTranscription factor – many target genesItself is not sufficient to confer suppressive function A TGFβ does not induce regulatory function

FoxP3

CD4+CD25+FOXP3+

REGULATORY T CELLS

FUNCTIONS OF REGULATORY T CELLSFUNCTIONS OF REGULATORY T CELLS

•Maintenance of peripheral tolerance

•Prevention of autoimmunity

•Limiting inflammatory processes (asthma, inflammatory bowel diseases)

•Inhibit protection against infectious diseases

•Limit immune responses to tumors

MECHANISM

Intrinsic and extrinsic regulation

Various inhibitory mechanisms

Cell contacts – Cytokines

Interaction with the target effector T cells

REGULATORY FUNCTION OF REGULATORY T LYMPHOCYTESREGULATORY FUNCTION OF REGULATORY T LYMPHOCYTES

IL-35

Inhibitory cytokines

TGFβ

IL-10

Cytolysis

Metabolic dysregulation Inhibition of dendritic cell maturation

Descreased cytokine production (IL-2)Adenosin around the cell

cAMP transfer

Indolamin2,3-dioxigenaseLAG-3 – CD4 homologTreg : effektor T cell = 1 : 8Treg : DC = 1 : 0,8

THE ROLE OF IL-35 IN THE FUNCTION OF REGULATORY T CELLSTHE ROLE OF IL-35 IN THE FUNCTION OF REGULATORY T CELLS

Induced capability, the effector cell is involved

NOT ONLY A FUNCTION

•The molecular patterns of activated Treg cells are different in the presence and absence of effector cells

•The expression of EBI3 and IL-12α/p35 (IL-35) subunits is increased in the presence of effector T cells

•Treg cells in contact with effector cell act also on effector cells out of contact through IL-35

Initial T cell activation Sensed by Treg cells

Increased suppressive mechanisms

REGULATORY CELLS ARE ABLE TO CONTROL LOW LEVEL ACTIVATION