Download Immune Regulation, Tolerance, and Autoimmunity

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Immune Regulation, Tolerance, and
Autoimmunity
Mark S. Anderson, MD, PhD
UCSF
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Disclosures
• Research support from Juno
Therapeutics
• Consultant for Sanofi
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Lecture outline
• Principles of immune regulation
• Self-tolerance; mechanisms of central
and peripheral tolerance
• Inhibitory receptors of T cells
• Treg’s and IL-2
The immunological equilibrium: balancing
lymphocyte activation and control
Activation
Effector T cells
Normal: reactions
against pathogens
Inflammatory
disease, e.g.
reactions against self
Tolerance
Regulatory T cells
Controlled response to
pathogens
No response to self
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Central and peripheral tolerance to self
The principal fate
of lymphocytes that
recognize self antigens
in the generative organs
is death (deletion), BUT:
Some B cells may change
their specificity (called
“receptor editing”)
Some T cells may
differentiate into
regulatory (suppressor)
T lymphocytes
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011
c Elsevier
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Consequences of self antigen recognition in thymus
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011
c Elsevier
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What self antigens are seen in the
thymus?
• Ubiquitous cell-associated and circulating
proteins
• The thymus has a special mechanism for
displaying peripheral tissue antigens in
thymic medullary epithelial cells, where
they signal self-reactive thymocytes for
death
Consequences of AIRE mutation
• Human disease: autoimmune
polyendocrinopathy with candidiasis and
ectodermal dysplasia (APECED), also called
autoimmune polyendocrine syndrome (APS-1)
– Associated gene identified by positional cloning,
named AIRE (“autoimmune regulator”)
• Mouse knockout: autoantibodies against
multiple endocrine organs, retina
– Failure to express many self antigens in the
thymus --> failure of negative selection
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Deletion of self-reactive T cells in the thymus: 9
how are self antigens expressed in the thymus?
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8th edition, 2014
AIRE (autoimmune regulator) is a regulator of gene transcription
that stimulates thymic expression of many self antigens which are
largely restricted to peripheral tissues
NOD.Aire GW/+ mice develop
peripheral neuropathy (CIDP)
Sciatic Nerve
Peripheral T cell tolerance
Abbas, Lichtman and Pillai. Basic Immunology, 4th edition, 2014
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T cell anergy
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011
c Elsevier
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CTLA-4 competitively inhibits B7-CD28 engagement
APC
APC
B7
CD28
T Cell
B7
CTLA-4
T cell (activated
T cell or Treg)
Costimulation 
T cell activation
CTLA-4 blocks and removes
B7  lack of costimulation
 T cell inhibition
The B7:CD28 families
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8th edition, 2014
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Activation
• CD28-B7: initiation of immune
responses
• ICOS-ICOS-L: T cell help in
germinal center reactions (antibody
responses)
Inhibition
Major functions of selected B7-CD28
family members
• CTLA-4-B7: inhibits early T cell
responses in lymphoid organs
• PD-1:PD-L1,2: inhibits effector T
cell responses in peripheral tissues
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Blocking CTLA-4 promotes tumor rejection:
CTLA-4 limits immune responses to tumors
Administration of antibody that blocks CTLA-4 in
tumor-bearing mouse leads to tumor regression
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The PD-1 inhibitory pathway
• PD-1 recognizes two widely expressed
ligands (PD-L1, PD-L2)
• Knockout of PD-1 leads to autoimmune
disease (less severe than CTLA-4-KO)
• Role of PD-1 in T cell suppression in
chronic infections, tumors?
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T cell “exhaustion” in chronic viral infections
Naïve CD8+
T cells
Virus
Effector
T cells
Acute infection:
clearance of virus
Memory T
cells:
enhanced
antiviral
responses
Chronic infection:
persistence of virus
Exhausted T cells: inability to
respond to virus
(expression of inhibitory
receptors, e.g. CTLA-4, PD-1)
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Actions of PD-1
• PD-1 attenuates TCR signaling in
responding T cells
• Limits harmful consequences of chronic
stimulation with persistent antigen (self,
tumors, chronic viral infections)
• Greater role in CD8 than in CD4 T cells
• Also expressed on follicular helper T
cells; function?
Checkpoint blockade for cancer immunotherapy
e.g. ipilimumab
Ribas A. N Engl J Med 2012;366:2517-2519.
Checkpoint blockade for cancer immunotherapy
e.g. ipilimumab
Ribas A. N Engl J Med 2012;366:2517-2519.
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e.g. nivolumab, pembrolizumab
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Risks of blocking CTLA-4 or PD-1
• Blocking a mechanism of self-tolerance
leads to:
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Risks of blocking CTLA-4 or PD-1
• Blocking a mechanism of self-tolerance
leads to:
• Autoimmune reactions (a new cottage
industry for clinicians?)
– Colitis and dermatitis are common
– Vitiligo, Endocrinopathies, hepatitis less
common but described
– Severity of adverse effects has to be
balanced against potential for treating
serious cancers
– Less severe with anti-PD1 antibody
Regulatory T cells
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 8th edition, 2014, Elsevier
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Properties of regulatory T cells
• Phenotype: CD4+, high IL-2 receptor
(CD25), low IL-7 receptor, Foxp3
transcription factor; other markers
• Essential features of stable Tregs:
– Foxp3 expression: requires demethylated noncoding CNS2 sequence in promoter
– CD25 (IL-2Ra) expression: IL-2 is a
necessary survival factor
– CTLA-4 expression: required for suppressive
function of most Tregs
– (Inability to produce IL-2)
Take home messages
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The significance of Foxp3+ Tregs
• Genetic evidence: Foxp3 mutations -->
autoimmune disease (IPEX); in mice,
disease can be corrected by providing
normal Foxp3+ cells
• Do defects in Foxp3+ Tregs or
resistance to Treg-mediated suppression
contribute to common autoimmune
diseases?
– Inconsistent and variable data
Mechanisms of action of Foxp3+ Tregs
• CTLA-4 on Tregs removes B7 on APCs,
reduces CD28 engagement and T cell
activation
– Genetic deletion of CTLA-4 in Foxp3+ cells
results in severe systemic autoimmunity and
lymphoproliferation
• Inhibitory cytokines produced by Tregs
(TGF-b, IL-10, others?) suppress
immune responses (DCs, Macs, T cells)
– IL-10 deletion in Foxp3+ cells results in
colitis
– IL-10 is also produced by Foxp3- cells
• Consumption of IL-2
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Regulatory T cells
• Explosion of information about the
generation, properties, functions and
significance of these cells
• Will cellular therapy with ex vivo
expanded Treg become a reality?
• Therapeutic goal: induction or activation
of Treg in immune diseases
Take home messages
The therapeutic potential of
regulatory T lymphocytes
• Cell transfer of autologous Tregs to
suppress immune responses
– Grow up patient’s Tregs ex vivo
– Ongoing clinical trials in graft rejection, T1D
show it is safe
– In one study of liver Tx, single infusion of
Tregs resulted in tolerance (withdrawal of
immunosuppression) in 7/10 patients (vs ~10%
historically)
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Functions of Interleukin-2: the dogma
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The unexpected biology of IL-2
• Interleukin-2 is the prototypic T cell
growth factor (TCGF), required for
initiating clonal expansion of T cells in
response to antigen
• BUT: knockout of IL-2 or the a or b
chain of the IL-2R results not in immune
deficiency but in systemic autoimmunity
and lymphoproliferation
Dual roles of IL-2 in T cell responses
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Surprising conclusion from knockout mice: the non-redundant
function of IL-2 is in controlling immune responses
Take home messages
due to IL-2R signalli
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PI3K–AKT and STA
effector T cells in re
and IL-2, TReg cells —
levels inhibit the P
way 43,44 — may be
signalling (FIG. 2).
In vivo experime
ings. At doses of IL-
Differential effects of IL-2 on
Teff vs Treg
mTOR
mTOR
Response
ctor
Reg
c ll
100
80
60
40
20
0
0.01
0.1
1
10
100
80
60
20
0
0.01
0.1
IL-2 IU ml–1
Fold increase in the number
of cells over baseline
Fold increase in the number
of cells over baseline
1
0
Baseline
5 days of
low-dose IL-2
1
10
100
1,000
IL-2 IUml–1
In vivo sensitivity to IL-2
2
IL-2 international units
are expanded compa
and they express hig
are more suppressiv
clonal expansion nor
T cells or of NK cells
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100 1,000
3
TReg cells
E ector T cells
In vitro sensitivity to IL-2
STAT5 phosphorylation (%)
STAT5 phosphorylation (%)
b
c ll
Response
3
2
1
0
Baseline
5 days of
low-dose IL-2
IL‑2 in pat hophysi
The inflammatory d
ing IL-2 or function
and the production
but the specific eff
mouse strain. On th
nant phenotype is a
caused by erythrocy
C57BL/6 mice, the d
time, all Il2-knockou
bodies that are spec
self-antigens. Intere
duced even in germ
the colitis is largely
mice are made germ
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Pathogenesis of autoimmunity
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Therapy of immune disorders: rational approaches target 36
lymphocyte activation and subsequent inflammation
Autoimmune diseases
• Experimental models are revealing
pathways of immune regulation
• But experimental animals are often
inadequate models of human diseases
• Improving technologies for human genetic
and phenotypic analyses are enabling
studies of patients
• Challenges:
– Defining which mechanisms of immune
tolerance fail in different autoimmune
diseases
– Using this knowledge to develop therapies
Take home messages
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The landscape of T cell activating and
inhibitory receptors: More to come?
TIGIT
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