1. NEGATIVE REGULATION OF THE IMMUNE SYSTEM

2. 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

3. 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

4. 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

5. 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.

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

7. 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.

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

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

10. REGULATORY T CELLS

11. 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

12. 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

13. 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

14. 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

15. REGULATORY CELLS ARE ABLE TO CONTROL LOW LEVEL ACTIVATION