Immune Tolerance. Kyeong Cheon Jung. Department of Pathology Seoul National University College of Medicine

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1 Immune Tolerance Kyeong Cheon Jung Department of Pathology Seoul National University College of Medicine Immune tolerance Unresponsiveness to an antigen that is induced by previous exposure to that antigen Self tolerance: The normal lack of the ability to produce an immunological response to autologous (self) antigens. Transplantation tolerance: the specific absence of a destructive immune response to a transplanted tissue in the absence of immunosuppression Abbas: Cellular and Molecular Immunology 7E 1

2 Self tolerance Central tolerance Negative selection Receptor editing Generation of regulatory T cells Peripheral tolerance Clonal anergy Clonal deletion Regulatory T cells T-T interaction Abbas: Cellular and Molecular Immunology 7E Thymocyte Development Nat Immunol. 2006;7:

3 Central tolerance of T cells Regulaotry T cells Negative selection: mtec vs DCs Trends Immunol 2002, 23:

4 AIRE (Autoimmune Regulator) A gene or its encoded protein, which functions to stimulate expression of peripheral tissue protein antigens in medullary thymic epithelial cells AIRE & promiscuous gene expression Trends Immunol. 2002, 23:

5 AIRE & central Tolerance Role of AIRE in self antigen presentation Induction of promiscuous gene expression Induction of antigen presentation Role of AIRE + mtec Clonal deletion Treg induction Role of DC Uptake & presentation of antigen from AIRE + mtec negative selection Defect in AIRE gene autoimmune polyendocrinopathycandidiasisectodermaldystrophy (APECED), autoimmune polyglandular syndrome type 1 (APS-1) AIRE knock-out mouse 5

6 Manifestation of APS-1 Peripheral tolerance Clonal anergy: functional unresponsiveness Clonal deletion: cell death Active suppression by regulatory T cells T-T interaction 6

7 T cell anergy in the absence of costimulatory signals Costimulatory vs. inhibitory moleccules Costimulation (APC : T cell) B7-2 (CD86) : CD28 B7-1 (CD80) : CD28 CD40 : CD40L (CD154) ICOSL : ICOS CD70 : CD27 OX40L (CD134L) : OX40 (CD134) 4-1BBL : 4-1BB Inhibition (APC : T cell) B7-2 : CTLA-4 B7-1 : CTLA-4 PD-L1, PD-L2: PD-1 7

8 Circ Res. 2008, 103: CTLA-4/B7 vs. CD28/B7 Interaction Immunity, 1997, 7:

9 Immune dysregulation in human subjects with heterozygous mutations in CTLA4 Science, 2014, 345: Development of abatacept & belatacept J Allergy Clin Immunol 2008, 121:299 9

10 PD-1 PD-L pathway contributes directly to T cell dysfunction during chronic viral infection Nat Immunol 2007, 8:239 PD-L1 KO mice infected with chronic form of virus Nature 2006, 439:

11 PD-1 PD-L pathway in peripheral tolerance Am J Transplant. 2012;12: PD-1 signaling Immunol Rev 2010; 236:

12 Autoimmunity vs. anti-cancer immunity Anti-CTLA-4: Ipilimumab Anti-PD-1: Pembrozumab Adverse Events in Patients Receiving Anti PD-L1 Antibody N Eng J Med 2012, 266:

13 Vitiligo caused by anti-ctla-4 antibody therapy -induced-dermatologic-adverse-events.aspx Activation induced cell death (AICD) 13

14 Regulatory T cells: Subsets ntreg itreg Tr1 Th3 Phenotype CD CD GITR ? CTLA Foxp /+ - Cytokine secretion IL-10 +/ TGF Differentiation factors TGF-, RA IL-10, IFN- TGF-, IL-4 Suppression mechanism In vitro Diverse Diverse IL-10, TGF- TGF- In vivo Diverse Diverse IL-10, TGF- TGF- Modidifed from J Leukoc Biol. 2006, 80: & J Immunol 2003, 171: Basic mechanisms used by Treg cells *IDO, indoleamine 2,3-dioxygenase Nat Rev Immunol. 2008, 8:

15 Induction of itreg by cytokines TCR stimulation + IL-2 + TGF- itreg Retinoic acid TGF- + IL-6 Th17 TGF- + RA Treg CD103 + DC in gut: retinal dehydrogenase RA Treg (J Exp Med 2007, 204: ) Treg deficientyfoxp3 Mutation Foxp3 mutation In human: IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) Mouse: Scurfy mutant IL-2/IL-2R deficiency TGF deficiency 15

16 Immune regulation by T-T interaction Idiotype-anti-idiotype network TCR peptide presentation via MHC I or II molecules Immune suppression by anti-idiotype T cells Ergotype-anti-ergotype network CD25 or HSP60 peptide presentation by MHC class I or II molecules Immune suppression by anti-ergotypic T cells Induced tolerance Front Immunol. 2012;3:274 16

17 Autoimmunity vs. anti-cancer immunity Anti-CTLA-4: lpilimumab Anti-PD-1: Pembrozumab 17