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

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

200

400

600

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6Blood glucose level

100

Porcine C-peptide

0.4

6.4

3.7

1.23

Time (day)

Blo

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glu

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ve

ls (

mg

/dl)

Po

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p(n

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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