negative regulation of immune responses by various mechanisms itam-itim
TRANSCRIPT
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Negative regulation of immune responses by various mechanisms
ITAM-ITIM
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ITIM- mediated inhibition
ITIM recruited phosphatases inhibit the ITAM-induced kinase cascade
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B cell regulation CD22
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Sialic acid
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Phosphorilated ITIM motifs on FcγRIIbrecruits phosphatases to interfere signal
transduction
Inhibition of the signal transduction of B cell receptor
B cell
Ag Ag
B cell
FcγRII mediated B cell feedback regulation
FcγRIIbFcγRIIb
B cell regulation FcγRIIb
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T cell regulation CTLA4, PD-1(ITIM Like)
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NK cell regulation MHCI
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2B4/CD244/SLAMF4 ILT7/CD85g BLAME/SLAMF8 ILT11/LILRA5 BTLA Immunoreceptor Array Kit CD3 Integrin alpha 2b beta 3 CD3 epsilon Integrin beta 3/CD61 CD5 KIR/CD158 CD6 KIR2DL1/CD158a CD23/Fc epsilon RII KIR2DL2/CD158b1 CD28 KIR2DL3/CD158b2 CD31/PECAM-1 KIR2DL4/CD158d CD72 KIR2DL5/CD158f CD84/SLAMF5 KIR2DS1/CD158h CD229/SLAMF3 KIR2DS4/CD158i CD300a/LMIR1 KIR2DS5/CD158g CD300b/LMIR5 KIR3DL1 CD300c/LMIR2 KIR3DL2/CD158k CD300e/LMIR6 KIR3DL3/CD158z CD300f/LMIR3 KIR3DS1/CD158e2 CEACAM-1/CD66a KLRG1 CEACAM-3/CD66d LAIR1 CLEC-1 LAIR2 CLEC-2 LIR-8/CD85c CLEC-2A MDL-1/CLEC5A CRACC/SLAMF7 MICL/CLEC12A CTLA-4 NFAM1 DCAR/CLEC4B NKp30/NCR3 DCIR/CLEC4A NKp44/NCR2 Dectin-1/CLEC7A NKp46/NCR1 DNAM-1/CD226 NKp80/KLRF1 Fc epsilon RI alpha NTB-A/SLAMF6Fc epsilon RI beta/MS4A2 PD-1 Fc gamma RIII (CD16) PDCD6 FCAR/CD89 PILR-alphaFc gamma RI/CD64 Siglec-2/CD22 Fc gamma RII/CD32 Siglec-3/CD33 Fc gamma RII/RIII (CD32/CD16) Siglec-5/CD170 Fc gamma RIIA/CD32a Siglec-5/Siglec-14 Fc gamma RIIB/CD32b Siglec-6/CD327 Fc gamma RIIB/C (CD32b/c) Siglec-7/CD328 Fc gamma RIIC/CD32c Siglec-8 Fc gamma RIIIA/CD16a Siglec-9 Fc gamma RIIIB/CD16bSiglec-10 FCRL1/FcRH1 Siglec-11 FCRL2/FcRH2 Siglec-14 FCRL3/FcRH3 Siglec-16FCRL4/FcRH4 Siglec-E FCRL5/FcRH5 Siglec-F FCRL5/FCRL3 Siglec-G FCRL6/FcRH6Siglec-H G6b SIRP beta 1/CD172b ILT2/CD85j SLAM/CD150 ILT3/CD85k TIGIT ILT4/CD85d TREM-3 ILT5/CD85a TREML1/TLT-1 ILT6/CD85e TREML2/TLT-2
ITAM and/or ITIM containing receptors
ITAM/ITIM-mediated regulation is a general process
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Immune Tolerance
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Central and Peripherial tolerance
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Central tolerance
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++
1. The primary T cell pool is biased to MHC-specificity (V genes) 1-2% for one allotype
2. Focusing the T cell pool to self MHC recognition (+)
3. Elimination of useless and self agressive clones (-)
4. CENTRAL TOLERANCE
5. Focusing the T cell repertoire for recognition of non self
6. CD4+ and CD8+ T cell use the same TCR repertoire
7. Individualized T cell repertoire available in the periphery
8. CD4 and CD8 co-stimulatory molecules are involved in positive selection
αβTCR αβTCRCD4+ CD8+
SELECTION OF T LYMPHOCYTES IN THE THYMUS
UNDER THE CAPSULE
CORTEX
CORTEX/MEDULLA
IL-7-dependent proliferation
β+preTαCD4-CD8-
DN
CD4+CD8+DP
MEDULLA
TCRαβ
TCR(-) sMHC+sP sMHC+fP fMHC+fP
selection
– selection
–AICD
NO
PERIPHERAL TOLERANCE
AICD – Activation Induced Apoptosis
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POSITIVE SELECTION – Thymic education (no instruction for specificity)Low avidity interaction of MHC - self peptide - TCR Thymic epithelial cellsSelf peptide composition and concentration (foreign peptides are not present)Low peptide dose induces positive selection – special ligands80-90% of DN (CD4-CD8-) T cells is NOT positively selected PASSIVE CELL DEATH BY NEGLECTION
NEGATIVE SELECTION – Central self toleranceHigh avidity of MHC - self peptide - TCR interactionUbiquitous and abundant self antigens are present in the thymusHigh peptide dose induces negative selectionAny thymic antigen presenting cell: epithelial cells, bone marrow-derived macrophages, dendritic cells
THE GENERATION OF SELF MHC + FOREIGN PEPTIDE SPECIFIC T CELLS REQUIRES WEAK INTERACTION WITH SELF MHC + SELF PEPTIDE
SELF RESTRICTED AND TOLERANT PERIPHERAL T CELL REPERTOIREPHYSIOLOGICAL TRESHOLD
NOT COMPLETE
SELECTION OF THE T CELL REPERTOIRE – CENTRAL TOLERANCE
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tissues are represented promiscuous gene expression in thymic epithelial cells
AIRE transcription factor
autoimmune regulator (AIRE) protein. Mutations in the AIRE gene are the cause of a multiorgan autoimmune disease called the autoimmune polyendocrine syndrome (APS).
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Peripherial tolerance
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Peripherial tolerance
deletion, apoptosis
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Activation induced cell death
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NEGATIVE REGULATION OF T CELL RESPONSES
Days5 10 15 20 25 30
Naive lymphocytes
Number of antigen specific cells
Primary effectors
Secondary effectors
Memory
DIFFERENTIATION
AICD
EXPANSION
AICD
MEMORY
AICDActivation Induced Cell Death
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Signaling Pathways of AICD
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Ligand binding to TNFR1 és TNFR2 receptors triggers pro- and anti-apoptotic signalling pathways
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Elimination of effector T cells at the end of the immune response
Activation-induced cell death (AICD)
Sustained T cell activation induces pro-apoptotic signals
Expression of Fas, FasL, Bad, Bax is increased – CELL DEATHExpression of Bcl-2, FLIP is decreased – SURVIVAL decreased
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repeated stimulation of T cells by persistent antigens leads to the coexpression of the two molecules, a death- inducing receptor called Fas(CD95) and its ligand, Fas ligand(FasL)
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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 APOPTOSISFas receptor – Fas ligand interactions
T CELL HOMEOSTASIS SHUT OFF IMMUNE RESPONSES
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Anergy
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A B7 : CD28 receptor family
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ABBAS MIT 2013 Pécs
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The activation of naiv T cell requires costimultaionCostimulatory molecules are expressed only in professional antigen presenting cells
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Anergy
Absence of costimulation
or
Negative signal
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TCR activation in the absence of costimulation results in the degradation of key moleclues in TCR signaling
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B71/2
TAPC
CD28 activation
CTLA-4
ITIM
NEGATIVE REGULATION OF T CELL ACTIVATION BY CTLA-4
LATE EXPRESSION
CTLA4 has HIGHER AFFINITY TO B7 THAN TO CD28, but the amount of it is limited
CTLA4 1. Inhibition of ITAM signaling
2. Competition with CD28
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In general the activation of naiv T cells requires DC-mediated antigen presentation
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Normal tissue cells do not express MHC class IINO SIGNAL 1. for CD4+ Th activation
Normal tissue cells do not express co-stimulatory molecules and do not produce T cell differentiating cytokinesNO SIGNAL 2. for CD4+ Th activation
Migration of naive T lymphocytes to normal tissues is limitedAntigen presenting cells are not activated in normal tissues
NO SIGNAL 3. for CD4+ Th activation
PERIPHERAL TISSUES TOLERIZE THEMSELVES
PERIPHERAL TOLERANCEIMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY
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NEGATIVE REGULATION OF IMMUNE RESPONSES BY REGULATORY T CELLS
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The main role of regulatory T cells
ABBAS MIT 2013 Pécs
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Sakaguchi 2008
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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
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Regulatory T cells are normal T cells!MHC/peptide recognition--- self peptides!clonal proliferation, activation...mostly 95% CD4+ helper T cells
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Natural regulatory T cell
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Development of the CD25+CD4+ regulatory T cell lineage
TCR as polymorphic as for CD25- cellsSpecific to self antigens, MHC II restrictedRequires IL-2, Co-stimulation, CD28, B7
Foxp3 is a master regulatortransforms CD25 status
SchwartzNat Immunol 2005
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EFFECTOR CD4+ HELPER T LYMPHOCYTES SECRETE DIFFERENT CYTOKINES
Inflammatory cytokines
CELLULAR IMMUNE RESPONSE
Anti-inflammatory cytokines
HUMORAL IMMUNE RESPONSE
IFNγ, IL-2, TNF-β/LT
Th1 Th0
IL-4, IL-5, IL-10
Th2IL-4IFNγ
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Inducible Treg cells
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Sakaguchi 2008
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InducibleTreg requires TGF-β, IL2
TGF-β or blocking of TGF-β signals in T cells leads to a systemic inflammatory disease IL-2 receptor is knocked out develop autoimmunity
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The dependence of Treg cells on IL-2, which they cannot produce themselves but instead receive from conventional T cells, provides a negative feedback loop through which the ratio between Treg cells and conventional T cellsis controlled
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Mechanisms of Action of Regulatory T Cells
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1. produce IL-10 and TGF-bTGF-β • inhibits the proliferation and effector functions of T cells and the activation of
macrophages, neutrophils and endothelial cells• inhibits development of TH1 and TH2 subsets • promotes the development of the TH17 subset (in the presence of other cytokines)• stimulates production of IgA antibodies • promotes tissue repair IL10• inhibits the expression of costimulators and class II MHC molecules on
dendritic cells and macrophages • inhibits the production of IL-12 by activated dendritic cells and macrophages • inhibits macrophage and dendritic cell functions
2. inhibit the ability of APCs to stimulate T cells (binds to B7 molecules on APCs and either blocks these molecules or removes them by
internalizing them )
3. consume of IL-2
4. metabolism
5. cytolitic processes
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MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE FUNCTIONS
IL-35
Inhibitory cytokines
TGFβ
IL-10
Cytolysis
Metabolic disturbance Inhibition of T cell proliferation
Reduced cytokine production (IL-2)Peri-cellular adenosine
cAMP transfer
Indolamine-2,3 dioxigenaseLAG-3 – CD4 homologue
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CELL SURFACE ENZYMES OF REGULATORY T CELLS PRODUCE EXTRACELLULAR NUCLEOTIDES
Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase
Ecto-5’-nucleotidase
EBI3Ebstein-Barr virus induced gene 3
IL-27 and IL-35
Naiv T sejtek toborzása, aktiválása, polarizálása
CD4+CD25- effektor sejtek A2A receptort fejeznek ki
Peri-cellular/Szupresszív
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Treg constitutively downregulates the self presenting DC
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Possible Mechanisms of Treg-Mediated Suppression
Sakaguchi 2008
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ABBAS MIT 2013 Pécs
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ABBAS MIT 2013 Pécs
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A regulátor T-sejtek különálló fejlődési vonalat képviselnek és gátolják az autoreaktív T-sejtek aktivációját
CD25+ FoxP3+ sejtek
FoxP3-hiány: autoimmun betegség
IPEX: immune dysregulation polyendocrinopathy, enteropathy, X-linked syndrome
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Summary of peripherial tolerance:
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B cells tolerance
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B-sejt tolerancia
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The absence of T cell help / Treg cell siganal
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Peripherial tolerance
deletion, apoptosis