abul k. abbas ucsf · 2018-10-02 · abul k. abbas ucsf focis. 2 lecture outline ... of modern...
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Immune regulation and tolerance
Abul K. AbbasUCSF
FOCiS
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Lecture outline
• Self-tolerance; central and peripheral tolerance
• Inhibitory receptors of T cells
• Regulatory T cells
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Immunological tolerance
• Definition:
– unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen; antigen-specific (unlike “immunosuppression”)
• Significance:
– All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity
– Therapeutic potential: Inducing tolerance may be exploited to treat autoimmune and allergic diseases
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Where and when is self-tolerance induced?
Central tolerance Peripheral tolerance
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Consequences of self antigen recognition in thymus
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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
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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 (revealed by transcriptome analysis of normal vs AIRE-/- thymic epithelial cells)
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8Deletion of self-reactive T cells in the thymus:how are self antigens expressed in the thymus?
AIRE (autoimmune regulator) is a transcription factor that stimulates thymic expression of many self antigens which are largely restricted to peripheral tissues
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APCTCR
NaïveT cell
Immunogenic antigen
(microbe, vaccine)
Tolerogenicantigen (e.g.
self)
Effector and memory cells
Tolerance: functional inactivation or cell death, or sensitive to suppression
Antigen (peptide + HLA): signal 1
Costimulation(signal 2)
Peripheral tolerance 9
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Inhibitory receptors of T cells
• Prevent reactions against self antigens (their physiologic function)
• Suppress immune responses to some tumors, chronic infections (HCV, HIV)• Therapeutic application: checkpoint blockade
for cancer immunotherapy
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11The B7:CD28 families 11
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12Major functions of selected B7-CD28 family members
• CD28-B7: initiation of immune responses
• ICOS-ICOS-L: T cell help in germinal center reactions (antibodyresponses)
• CTLA-4-B7: inhibits early T cell responses in lymphoid organs
• PD-1:PD-L1,2: inhibits effector T cell responses in peripheral tissues
Act
ivation
Inh
ibition
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APCTCR
CD28
NaïveT cell
B7
B7-CD28interaction
B7-CTLA-4interaction
CTLA-4
Proliferation,differentiation
Functional inactivation
The opposing functions of CD28 and CTLA-4
Knockout of CTLA-4 in mice and mutation in humans results in immune dysregulation (lymphoproliferation, multi-organ inflammation)
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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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Action of PD-1
Normal response PD-1 engagement
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APC
TCR
NaïveT cell
Effector and memory T cells
CD28 B7
APC
CTLA-4
APC
Cell-intrinsic: Termination of response
Responding T cell
Regulatory T cell
APC
Responding T cell
Cell-extrinsic: Treg-mediated suppression of
response
Immune response
Actions of CTLA-4
Expression of CTLA-4
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APC
T Cell
CD28
B7
Costimulation T cell activation
CTLA-4 competitively inhibits B7-CD28 engagement
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APC APC
T Cell
CD28
B7
Costimulation T cell activation
B7
CTLA-4
CTLA-4 blocks and removes B7 lack of costimulation
T cell inhibition
CTLA-4 competitively inhibits B7-CD28 engagement
T cell (activated T cell or Treg)
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Functions of CTLA-4
• Limits activation of responding T cells
• Mediates suppressive function of regulatory T cells (Tregs)
• How does the T cell choose to use CD28 to be activated (e.g. with microbes) or CTLA-4 to shut down (e.g. with self Ag)?– Level of B7 expression and affinity of
receptors: Low B7 (e.g. when DC is displaying self or tumor antigen) --> engagement of high-affinity CTLA-4
– High B7 (e.g. after microbe encounter) --> engagement of lower affinity CD28
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Regulatory T cells
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Properties of regulatory T cells
• Phenotype: CD4+, high IL-2 receptor (CD25), Foxp3 transcription factor; other markers
• Essential features of stable Tregs: – Foxp3 expression: requires demethylated non-
coding 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)
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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
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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
– Commonly used assay for Treg function in humans bypasses the need for B7 and cannot measure this activity
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Mechanisms of action of Foxp3+ Tregs
• CTLA-4 on Tregs removes B7 on APCs, reduces CD28 engagement and T cell activation
• Inhibitory cytokines produced by Tregs(IL-10, others?) suppress immune responses (DCs, Macs, T cells) – IL-10 is especially important for regulating
mucosal immune responses (deletion of IL10 in Foxp3+ cells results in colitis)
• Consumption of IL-2
• Many others reported
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Role of Tregs in fetal tolerance
• In evolution, placentation developed at the same time as the ability to generate FoxP3+ peripheral Tregs
• Paternal antigens expressed in the fetus induce long-lived antigen-specific Tregs
• Elimination of fetal antigen-specific Tregs in mice results in fetal resorption
• Anatomic restriction of immune regulation?
• Role in humans? Are defects in regulatory memory the basis of recurrent fetal loss?
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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
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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
– Very little efficacy data
– Technically difficult, individualized
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The therapeutic potential of regulatory T lymphocytes
• Cell transfer of autologous Tregs to suppress immune responses
• Administer antigen or cytokine in ways that preferentially induce Tregs?– Antigen without adjuvant?
– IL-2
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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
• Prediction: what will be the consequence of eliminating IL-2 or the IL-2 receptor?
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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 bchain of the IL-2R results not in immune deficiency but in systemic autoimmunity and lymphoproliferation
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Dual roles of IL-2 in T cell responses
Surprising conclusion from knockout mice: the non-redundant function of IL-2 is in controlling immune responses
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Therapeutic potential of IL-2: a revision
• IL-2 was originally used to boost immune responses in cancer, HIV infection (enhancing effector and memory T cells) • IL-2 treatment can increase number and
functional activity if Tregs
• Use of IL-2 to boost Tregs: design IL-2 to bind to high-affinity CD25 • Low-dose IL-2 • Mutant IL-2 that binds preferentially to
CD25
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34Regulating immune responses: where are we?
• Elucidating the mechanisms of immune regulation is one of the dominant themes of modern Immunology; obvious relevance to immune-mediated inflammatory diseases, therapeutics, vaccines
• Already leading to new therapeutic strategies
• Continuing challenge is to establish the importance of control mechanisms in the development of inflammatory diseases