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NEGATIVE REGULATION OF THE
IMMUNE SYSTEM
NEGATIVE REGULATION IN THE IMMUNE SYSTEM
1. Decrease of antigen concentration in the course of the immune response
2. 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
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
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
4. 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
AICD
DIFFERENTIATION
Naive
lymphocytes
Memory
Primary
effectors
Number of antigen
specific cells
Secondary
effectors
EXPANSION
AICD
MEMORY
5
10
15
20
25
30
Days
IMMUNOGLOBULIN BINDING Fc RECEPTORS
FcγRI (CD64)
FcγRII (CD32)
IIa
Ib
IIc
IIb1 IIb2/IIb3
tetramer
FcεRII
Ca 2+
trimer
Ca 2+
Ca 2+
SS
SS
-S-S-
SS
SS
SS
SS
SS
SS
SS
SS
SS
SS
Iγ-γ
SS
SS
Ia
FcεRI
-S-S-
-S-S-
-S-S-
SS
SS
ITAM
α
FcγRIII (CD16)
SS
SS
SS
SS
SECRETORY
PIECE
SS
SS
γ-γ α
SS
IIIb
SS
SS
IIIa
poli-Ig re ceptor
SS
SS
α γ-γ
FcRI
SS
IIIaζ-ζ IIIaζ-γ IIIaγ-γ IIIaβ
β γ-γ
SS
ITIM
SS
ITAM
SS
ITAM
ITAM
IgG Fc receptors
Ig supergene family, MIRR
Activating receptor
ITAM
Expression
Inhibitory receptor
ITIM
Expression
Fc receptorok
Ig supergene family
BCR*
B cell
TCR,* CD3*
T cell
FcRIa (CD64)
FcRI*
Macrophage, DC
(internalization)
FcRIIa (CD32)
Macrophage, DC
(internalization)
FcRIIIa (CD16)
FcRI* vagy *
NK cell (ADCC)
FcRI, FcRI*
Mast cell (ADCC)
FcRIIb (CD32)
B cell
FcRIIb (CD23b)
FcRIIa (CD23a)
B cell
Human KAR
Human KIR
NK and T cell
C-type lectin
MHC I receptorok
Ig supergene family
C-típusú lektin
Egér KIR
Human NKG2C/D
NK and regulatory T cell
Human NKG2A/B
NK and regulatory
T cell
BCR
CD22
B cell
CD28
CTLA-4
T cell
Other receptors
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
FcRIIb
ITIM
Costimulatory molecules also associate
with inhibitory receptors
T cell
Signal 1 +
2
2
Activated T cell
-- -- CD28/CTLA-4
CD28
B7
B7
CD28 cross linked by B7
Co-stimulation
induces CTLA-4
Cross-linking of CTLA-4
by B7 inhibits co-stimulation
and inhibits T cell activation
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
4+
CD
Th1
B
CD4+
Th1
Fas L
APC
F as
C D 8+
Tc
T CELL HOMEOSTASIS
SHUT OFF IMMUNE RESPONSES
REGULATORY T CELLS
REGULATORY T CELLS
MARKERS OF THYMUS DERIVED NATURAL Treg CELLS
CD4+CD25+FOXP3+
GITR
CTLA4
B7 ligand
Treg
FoxP3
CD25
IL-2Rα
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
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
Descreased cytokine production (IL-2)
Adenosin around the cell
cAMP transfer
Inhibition of dendritic cell maturation
Indolamin2,3-dioxigenase
LAG-3 – CD4 homolog
Treg : effektor T cell = 1 : 8
Treg : DC = 1 : 0,8
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