Download Immunopathology

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



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
Nat Immunol. 2006;7:338-334
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



Role of AIRE+ mTEC



Induction of promiscuous gene expression
Induction of antigen presentation
Clonal deletion
Treg induction
Role of DC

Uptake & presentation antigen from AIRE+ mTEC 
negative selection
Defect in AIRE gene


autoimmune polyendocrinopathycandidiasis-ectodermaldystrophy
(APECED), autoimmune polyglandular
syndrome type 1 (APS-1)
AIRE knock-out mouse
Defect in central selection: Inefficient
antigen presentation

H-2U strains

I-Ag7 in NOD mice

SKG mouse  ZAP70
mutation  RA
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
Inhibition
(APC : T cell)
Costimulation
(APC : T cell)






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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 in peripheral
tolerance
Am J Transplant. 2012;12:2575-87
Activation induced cell death (AICD)
Regulatory T cells: Subsets
nTreg
iTreg
Phenotype
CD25
++
CD103
++
GITR
++
++
CTLA-4
+++
+++
Foxp3
++
++
Cytokine secretion
IL-10
+/++
TGF-
+
Differentiation factors
TGF-, RA
Suppression mechanism
In vitro
Diverse
Diverse
In vivo
Diverse
Diverse
Tr1
Tr3
+
+
-/+
+
?
++
-
+++
+
+
+++
IL-10, IFN- TGF-, IL-4
IL-10, TGF-
IL-10, TGF-
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
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
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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
Suppression
-Qa1
CD8 T
Autoimmunity vs. anti-cancer
immunity


Anti-CTLA-4: lpilimumab
Anti-PD-1: Pembrozumab
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