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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: 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
Regulaotry
T 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



Role of AIRE+ mTEC



Induction of promiscuous gene expression
Induction of antigen presentation
Clonal deletion
Treg induction
Role of DC

Uptake & presentation of antigen from AIRE+ mTEC 
negative selection
Defect in AIRE gene


autoimmune
polyendocrinopathycandidiasisectodermaldystrophy
(APECED), autoimmune
polyglandular syndrome
type 1 (APS-1)
AIRE knock-out mouse
Defect in central tolerance: Qualitative
difference
B6
SJL
EAE
Brain
Thymus
Nat Med 2000, 6:56-61
Manifestation of APS-1
Peripheral tolerance

Clonal anergy: functional unresponsiveness

Clonal deletion: cell death

Active suppression by regulatory T cells

T-T interaction
T cell anergy in the absence of costimulatory signals
Costimulatory vs. inhibitory
moleccules
Inhibition
(APC : T cell)
Costimulation
(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-L1, PD-L2: PD-1
Circ Res. 2008, 103:1220-1231
CTLA-4/B7 vs. CD28/B7 Interaction
Immunity, 1997, 7: 445-450
Immune dysregulation in human
subjects 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
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
Th3
+
+
-/+
+
?
++
-
+++
+
+
+++
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
Differential TCR signalling in negative
selection and Treg cell differentiation
©2012 by Cold Spring Harbor Laboratory Press
Yan Xing, and Kristin A. Hogquist Cold Spring Harb
Perspect Biol 2012;4:a006957
Basic mechanisms used by Treg cells
*IDO, indoleamine 2,3-dioxygenase
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

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
Lack of immune cell infiltration in islet
xenograft of MD-3-treated group
D
H&E
Control
Ab
MD-3
Insulin
CD3
CD68
600
6
P o r c in e C - p e p tid e
5
4
3 .7
6 .4
400
B lo o d g lu c o s e le v e l
3
2
1 .2 3
200
1
100
0 .4
0
0
0
100
200
300
T im e ( d a y )
400
500
600
P o r c in e c - p e p ( n g /m l)
B lo o d g lu c o s e le v e ls (m g /d l)
Long-term survival of islet xenograft in
Rhesus monkeys via combined therapy
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