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Immune ToleranceImmune Tolerance
Kyeong Cheon JungDepartment of PathologySeoul National University College of Medicine
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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
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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
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Thymocyte Development
Nat Immunol. 2006;7:338-334
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Central tolerance of T cells
RegulaotryT cells
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Negative selection: mTEC vs DCs
Trends Immunol 2002, 23:364-371
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AIRE (Autoimmune Regulator)
A gene or its encoded protein, which functions to stimulate expression of peripheral tissue protein antigens in medullary thymic epithelial cells
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AIRE & promiscuous gene expression
Trends Immunol. 2002, 23:364-71
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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
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Defect in AIRE gene
autoimmune polyendocrinopathy-candidiasis-ectodermaldystrophy (APECED), autoimmune polyglandular syndrome type 1 (APS-1)
AIRE knock-out mouse
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Defect in central tolerance: Qualitative difference
Nat Med 2000, 6:56-61
B6
SJL
Thymus
Brain
EAE
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Manifestation of APS-1
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Clonal anergy: functional
unresponsiveness
Clonal deletion: cell death
Active suppression by regulatory T
cells
T-T interaction
Peripheral tolerance
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T cell anergy in the absence of co-stimulatory signals
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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)
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Circ Res. 2008, 103:1220-1231
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CTLA-4/B7 vs. CD28/B7 Interaction
Immunity, 1997, 7: 445-450
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Immune dysregulation in humansubjects with heterozygous mutations in CTLA4
Science, 2014, 345: 1623-1627
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Development of abatacept & belatacept
J Allergy Clin Immunol 2008, 121:299
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PD-1–PD-L pathway contributes directly to T cell dysfunction during chronic viral infection
Nat Immunol 2007, 8:239
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PD-L1 KO mice infected with chronic form of virus
Nature 2006, 439:682-687
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PD-1–PD-L pathway in peripheral tolerance
Am J Transplant. 2012;12:2575-87
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PD-1 signaling
Immunol Rev 2010; 236:219-242
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Autoimmunity vs. anti-cancer immunity Anti-CTLA-4: Ipilimumab Anti-PD-1: Pembrozumab
http://melanomamissionary.blogspot.com
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Adverse Events in Patients Receiving Anti–PD-L1 Antibody
N Eng J Med 2012, 266:2455-2465
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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
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Activation induced cell death (AICD)
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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
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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
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Basic mechanisms used by Treg cells
Nat Rev Immunol. 2008, 8:523-532
*IDO, indoleamine 2,3-dioxygenase
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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)
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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
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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
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Induced tolerance
Front Immunol. 2012;3:274
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Arrest of DC maturation in semimature stage via MD-3 Ab treatment- in vitro surface molecules -
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Arrest of DC maturation in semimature stage via MD-3 Ab treatment - in vitro cytokine secretion -
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Prolongation of porcine islet xenograft survival in humanize mice via MD-3 treatment
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ControlAb
MD-3
H&E Insulin CD3 CD68D
Lack of immune cell infiltration in islet xenograft of MD-3-treated group
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Long-term survival of islet xenograft in Rhesus monkeys via combined therapy
0 100 200 300 400 500 6000
200
400
600
0
1
2
3
4
5
6Blood glucose level
100
Porcine C-peptide
0.4
6.4
3.7
1.23
Time (day)
Blo
od
glu
co
se
le
ve
ls (
mg
/dl)
Po
rcin
e c
-pe
p(n
g/m
l)
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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