Immune ToleranceImmune Tolerance

Kyeong Cheon JungDepartment of PathologySeoul 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

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;7:338-334

Central tolerance of T cells

RegulaotryT cells

Negative selection: mTEC vs DCs

Trends Immunol 2002, 23:364-371

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 of 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

Nat Med 2000, 6:56-61

B6

SJL

Thymus

Brain

EAE

Manifestation of APS-1

Clonal anergy: functional

unresponsiveness

Clonal deletion: cell death

Active suppression by regulatory T

cells

T-T interaction

Peripheral tolerance

T cell anergy in the absence of co-stimulatory signals

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)

Circ Res. 2008, 103:1220-1231

CTLA-4/B7 vs. CD28/B7 Interaction

Immunity, 1997, 7: 445-450

Immune dysregulation in humansubjects with heterozygous mutations in CTLA4

Science, 2014, 345: 1623-1627

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-L1 KO mice infected with chronic form of virus

Nature 2006, 439:682-687

PD-1–PD-L pathway in peripheral tolerance

Am J Transplant. 2012;12:2575-87

PD-1 signaling

Immunol Rev 2010; 236:219-242

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

http://melanomamissionary.blogspot.com

Adverse Events in Patients Receiving Anti–PD-L1 Antibody

N Eng J Med 2012, 266:2455-2465

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

Activation induced cell death (AICD)

Regulatory T cells: Subsets nTreg iTreg Tr1

Th3

PhenotypeCD25 ++ - + +CD103 - ++ - -GITR ++ ++ - ?CTLA-4 +++ +++ + ++Foxp3 ++ ++ -/+ -

Cytokine secretionIL-10 +/- ++ +++ +TGF- + + +++

Differentiation factors TGF-, RA IL-10, IFN- TGF-, IL-4Suppression 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

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

Basic mechanisms used by Treg cells

Nat Rev Immunol. 2008, 8:523-532

*IDO, indoleamine 2,3-dioxygenase

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)

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

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

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

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

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

ControlAb

MD-3

H&E Insulin CD3 CD68D

Lack of immune cell infiltration in islet xenograft of MD-3-treated group

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

0 100 200 300 400 500 6000

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6Blood glucose level

100

Porcine C-peptide

0.4

6.4

3.7

1.23

Time (day)

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/dl)

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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