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 Transplantation tolerance Abbas: Cellular and Molecular Immunology 7E

Self tolerance Central tolerance Peripheral tolerance Negative selection 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 CD44+CD25- CD44+CD25+ CD44-CD25+ CD44-CD25-

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, 23:364-71

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 antigen from AIRE+ mTEC  negative selection

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

Defect in central tolerance: Qualitative difference B6-PLP deficient B6 SJL Thymus Brain Nat Med 2000, 6:56-61

Defect in central selection: Inefficient antigen presentation H-2U strains I-Ag7 in NOD mice SKG mouse  ZAP70 mutation  RA SNP of PTPN22 gene (1p13): 1858C>1858T allele Nat Genet. 2005, 37:1300-1302

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

T cell anergy by costimulation blockade

Costimulatory vs. inhibitory moleccules Costimulation (APC : T cell) Inhibition (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 B7-2 : CTLA-4 B7-1 : CTLA-4 PD-L : PD-1

Circ Res. 2008, 103:1220-1231

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

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

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

PD-1–PD-L pathway controls autoimmunity Nat Immunol 2007, 8:239

Activation induced cell death (AICD)

Regulatory T cells: Subsets nTreg iTreg Tr1 Tr3 Phenotype CD25 ++ - + + CD103 - ++ - - GITR ++ ++ - ? CTLA-4 +++ +++ + ++ Foxp3 ++ ++ -/+ - 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, 80:458-470 & J Immunol 2003, 171:6323-6327

Basic mechanisms used by Treg cells Nat Rev Immunol. 2008, 8:523-532

Foxp3 Mutation In human: IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) Mouse: Scurfy mutant Defect in CD25+CD4+ Treg development

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)

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

-idiotypic CD4+ T -Qa1 CD8 T Suppression