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
Transplantation tolerance
Abbas: Cellular and Molecular Immunology 7E

3. 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

4. Thymocyte Development
Nat Immunol. 2006;7:

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

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

7. 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

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

9. Defect in central selection: Inefficient antigen presentation
H-2U strains
I-Ag7 in NOD mice
SKG mouse  ZAP70 mutation  RA
Nat Genet. 2005, 37:

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

11. T cell anergy by costimulation blockade

12. 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

13. Circ Res. 2008, 103:

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

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

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

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

18. Activation induced cell death (AICD)

19. Regulatory T cells: Subsets
nTreg iTreg Tr1 Tr3
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:

20. Basic mechanisms used by Treg cells
Nat Rev Immunol. 2008, 8:

21. 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: )

22. Treg deficientyFoxp3 Mutation
In human: IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome)
Mouse: Scurfy mutant
IL-2/IL-2R deficiency
TGF deficiency

23. 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

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

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