NEGATIVE REGULATION OF THE IMMUNE SYSTEM

NEGATIVE REGULATION IN THE IMMUNE SYSTEM Decrease of antigen concentration in the course of the immune response Inhibition of B lymphocyte activation - antibody feedback Cross linking of BCR with FcRIIB (CD32) by antigen-antibody complex ITIM-induced negative signaling of B cell activation - phosphatases B cells without T cell help are excluded from follicles 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 stimulation 4. Inhibition T lymphocyte activation Anergy of CD4+ T lymphocytes Late in the immune response activated T cells express CTLA-4, the ligand of B7 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

Number of antigen specific cells NEGATIVE REGULATION OF IMMUNE RESPONSES AICD DIFFERENTIATION Naive lymphocytes Memory Primary effectors Secondary effectors Number of antigen specific cells EXPANSION AICD MEMORY

IMMUNOGLOBULIN BINDING Fc RECEPTORS Ig supergene family, MIRR FcγRI (CD64) FcγRII (CD32) FcεRI FcεRII Iγ-γ α β γ-γ α γ-γ FcγRIII (CD16) FcRI IIIaζ-ζ IIIaζ-γ IIIaγ-γ IIIaβ γ-γ α IgG Fc receptors Ig supergene family, MIRR

ACTIVATING AND INHIBITORY RECEPTORS IN THE IMMUNE SYSTEM Activating receptor ITAM Expression Inhibitory receptor ITIM Fc receptorok Ig supergene family BCR* B cell TCR,* CD3* T cell FcRIa (CD64) FcRI* Macrophage, DC (internalization) FcRIIa (CD32) FcRIIb (CD32) FcRIIIa (CD16) FcRI* vagy * NK cell (ADCC) FcRI, FcRI* Mast cell (ADCC) C-type lectin FcRIIb (CD23b) FcRIIa (CD23a) MHC I receptorok Human KAR Human KIR NK and T cell C-típusú lektin Egér KIR Human NKG2C/D NK and regulatory T cell Human NKG2A/B Other receptors BCR CD22 CD28 CTLA-4 MIRR Multisubunit Immune Recognition Receptors The ligand binding and signal transducing subunits are separated, they co-localize in membrane microdomains.

NEGATIVE REGULATION OF B LYMPHOCYTES BY IMMUNE COMPLEXES ITAM ITIM FcRIIb

Costimulatory molecules also associate with inhibitory receptors CD28 T cell CD28 Activated T cell Cross-linking of CTLA-4 by B7 inhibits co-stimulation and inhibits T cell activation - 2 Signal 1 + /CTLA-4 B7 B7 CD28 cross linked by B7 Co-stimulation induces CTLA-4 CTLA-4 binds CD28 with a higher affinity than B7 molecules The lack of signal 2 to the T cell shuts down the T cell response.

NEGATIVE REGULATION OF T CELL ACTIVATION BY CTLA-4 T APC CD28 B7 CTLA-4 LATE EXPRESSION HIGHER AFFINITY TO B7 THAN CD28

THE ROLE OF CD4+ T CELLS IN APOPTOSIS T CELL HOMEOSTASIS SHUT OFF IMMUNE RESPONSES

REGULATORY T CELLS

MARKERS OF THYMUS DERIVED NATURAL Treg CELLS REGULATORY T CELLS MARKERS OF THYMUS DERIVED NATURAL Treg CELLS CD4+CD25+FOXP3+ GITR CTLA4 B7 ligand Treg CD25 IL-2Rα FoxP3 CD127 IL-7Rα ↓ Treg differentiation, maintenance, function Transcription factor – many target genes Itself is not sufficient to confer suppressive function A TGFβ does not induce regulatory function

MECHANISM FUNCTIONS 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 LYMPHOCYTES Inhibitory cytokines Cytolysis TGFβ IL-10 IL-35 Metabolic dysregulation Inhibition of dendritic cell maturation Indolamin2,3-dioxigenase LAG-3 – CD4 homolog Treg : effektor T cell = 1 : 8 Treg : DC = 1 : 0,8 Descreased cytokine production (IL-2) Adenosin around the cell cAMP transfer

THE ROLE OF IL-35 IN THE FUNCTION OF REGULATORY T CELLS Initial T cell activation Sensed by Treg cells Increased suppressive mechanisms 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 Induced capability, the effector cell is involved NOT ONLY A FUNCTION

REGULATORY CELLS ARE ABLE TO CONTROL LOW LEVEL ACTIVATION