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

2. 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

3. 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

4. Thymocyte Development Nat Immunol. 2006;7:338-334

5. Central tolerance of T cells Regulaotry T cells

6. Negative selection: mTEC vs DCs Trends Immunol 2002, 23:364-371

7. AIRE (Autoimmune Regulator) A gene or its encoded protein, which functions to stimulate expression of peripheral tissue protein antigens in medullary thymic epithelial cells

8. AIRE & promiscuous gene expression Trends Immunol. 2002, 23:364-71

9. 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

10. Defect in AIRE gene autoimmune polyendocrinopathy- candidiasis- ectodermaldystrophy (APECED), autoimmune polyglandular syndrome type 1 (APS-1) AIRE knock-out mouse

11. Defect in central tolerance: Qualitative difference Nat Med 2000, 6:56-61 B6 SJL Thymus Brain EAE

12. Manifestation of APS-1

13. Clonal anergy: functional unresponsiveness Clonal deletion: cell death Active suppression by regulatory T cells T-T interaction Peripheral tolerance

14. T cell anergy in the absence of co- stimulatory signals

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

16. Circ Res. 2008, 103:1220-1231

17. CTLA-4/B7 vs. CD28/B7 Interaction Immunity, 1997, 7: 445-450

18. Immune dysregulation in human subjects with heterozygous mutations in CTLA4 Science, 2014, 345: 1623-1627

19. Development of abatacept & belatacept J Allergy Clin Immunol 2008, 121:299

20. PD-1–PD-L pathway contributes directly to T cell dysfunction during chronic viral infection Nat Immunol 2007, 8:239

21. PD-L1 KO mice infected with chronic form of virus Nature 2006, 439:682-687

22. PD-1–PD-L pathway in peripheral tolerance Am J Transplant. 2012;12:2575-87

23. PD-1 signaling Immunol Rev 2010; 236:219-242

24. Autoimmunity vs. anti-cancer immunity Anti-CTLA-4: Ipilimumab Anti-PD-1: Pembrozumab http://melanomamissionary.blogspot.com

25. Adverse Events in Patients Receiving Anti–PD-L1 Antibody N Eng J Med 2012, 266:2455-2465

26. Vitiligo caused by anti-CTLA-4 antibody therapy http://www.ascopost.com/issues/october-15,-2013/how-to-recognize-and-manage-ipilimumab -induced-dermatologic-adverse-events.aspx

27. Activation induced cell death (AICD)

28. Regulatory T cells: Subsets nTregiTregTr1Th3 Phenotype CD25++-++ CD103-++-- GITR++++-? CTLA-4+++++++++ Foxp3++++-/+- Cytokine secretion IL-10+/-++++++ TGF-  +++++ Differentiation factors TGF- , RAIL-10, IFN-  TGF- , IL-4 Suppression mechanism In vitroDiverse Diverse IL-10, TGF-  TGF-  In vivoDiverse Diverse IL-10, TGF-  TGF-  Modidifed from J Leukoc Biol. 2006, 80:458-470 & J Immunol 2003, 171:6323-6327

29. Yan Xing, and Kristin A. Hogquist Cold Spring Harb Perspect Biol 2012;4:a006957 ©2012 by Cold Spring Harbor Laboratory Press Differential TCR signalling in negative selection and Treg cell differentiation

30. Basic mechanisms used by Treg cells Nat Rev Immunol. 2008, 8:523-532 *IDO, indoleamine 2,3-dioxygenase

31. 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, 204:1757-1764)

32. 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

33. 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

34. Induced tolerance Front Immunol. 2012;3:274

35. Arrest of DC maturation in semimature stage via MD-3 Ab treatment - in vitro surface molecules -

36. Arrest of DC maturation in semimature stage via MD-3 Ab treatment - in vitro cytokine secretion -

37. Prolongation of porcine islet xenograft survival in humanize mice via MD-3 treatment

38. Control Ab MD-3 H&EInsulinCD3CD68 D Lack of immune cell infiltration in islet xenograft of MD-3-treated group

39. Long-term survival of islet xenograft in Rhesus monkeys via combined therapy

40. 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