Immune Regulation and Tolerance

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Immune Regulationand Tolerance
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Immunoregulation A balance between activation
and suppression of effector cells to achieve an
efficient immune response without damaging the
host.
Significance The induction of tolerance may be
exploited to prevent graft rejection, to treat
autoimmune and allergic diseases, and to prevent
immune responses in gene therapy.
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Important features of immunoregulation

1. Antigen specific affects T or B lymphocytes
2. Tolerance vs. activation? Determined by the
   nature of antigen and associated stimuli, and
   when and where the antigen is encountered

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Mechanisms of unresponsiveness Immunological
Ignorance
Normal response
Proliferation and differentiation
Mechanisms of unresponsiveness
Antigen/lymphocyte barrier
Mechanisms of autoimmunity
Tissue abnormalities contributing to release and
presentation of self antigens.
Disease models
Sympathetic ophthalmia, experimental allergic
encephalomyelitis (EAE)
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Mechanisms of unresponsiveness Central
tolerance in B and T cells (I) Clonal Deletion
Self antigen presented in generative lymphoid
organs
Deletion of immature lymphocytes strongly
recognizing self antigens present in generative
organs
Lymphoid precursor
Survival of clones which are only moderately
responsive to self antigens present in generative
organs forms T cell repertoire
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• AIRE Autoimmune regulator.
• Transcription factor.
• Expressed at a high level by thymic medullar
  epithelium
• cells.
• Autosomal recessive mutation leads to autoimmune
• polyendocrine syndrom - type 1 (APS-1)
• Inactivation of aire abolishes expression of
  tissue specific
• genes in thymic medulla.

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aire -/-
WT
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Mechanisms of unresponsiveness Central
tolerance in B cells (II)Receptor editing
bone marrow
pre-B

• rearrangement

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• Maturation of clones
• Non-reactive to soluble-
• low-affinity to soluble-
• self-reactive to monovalent-
• antigens in bone marrow

further rearrangement
immature B
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B follicle
T cell zone
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B220
Moma-1
Spleen artery
TCR
Self antigens
90
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Mechanisms of unresponsiveness Peripheral
tolerance in B cells (I) Follicular exclusion
- B cells binding to autoantigens in the
periphery may be excluded from follicles -
Excluded B cells undergo apoptosis
mechanisms for elimination is independent of Fas,
T cells. - Rapid elimination depends on the
presence of a normal repertoire of B cells
competition between B cells (for limited
survival factors?)
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BAFF TNF family cytokine, critical B cell
survival factor.
BAFF reduction leads to a decrease in peripheral
B cell numbers Over-expression of BAFF results
in autoimmune diseases (SLE).
BAFF receptor expressed on mature B cells.
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Mechanisms of unresponsiveness Peripheral
tolerance in B cells (II) Anergy
Immunogenic signaling
Tolerogenic signaling
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Anergic B cells can respond to Stronger antigens
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The two-signal requirement for T cell activation
Microbial antigen presented by APC
TCR
MHC
Signal 1
APC
Signal 2
B7
Costimulatory Receptor (CD28)
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The role of co-stimulation in T cell activation
Antigen recognition
T cell response
Resting APC (costimulator- deficient)
No response
Activation of APC Innate immune response
Activated APC increased expression of
costimulators, secretion of cytokines
T cell proliferation And differentiation
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Mechanisms of unresponsiveness Peripheral
tolerance in T cells (II) Anergy
T cell response
Stimulation with antigens
Pretreatment of T cells
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Molecular basis of anergy in T lymphocytes
TCR
CD3z
P

• PROXIMAL
• EVENTS
• - Reduced tyrosine
• phosphorylation
• - Reduced Ca influx

Zap 70
GROWTH FACTORS
NUCLEAR EVENTS - no induction of NFkB JNK
activities
CELL CYCLE
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Co-stimulatory pathways

• CD28 interacts with CD80 (B7-1) CD86 (B7-2) to
• initiate T cell responses.
• Preferentially expressed in naive T cells
• ICOS (CD28 homolog) stimulate effector T cell
  responses.
• Preferentially expressed in activated T cells
• CTLA-4 and PD-1 negatively regulate T cell
  activation

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Mechanisms of unresponsiveness Peripheral
tolerance in T cells (II) Anergy
T cell response
Stimulation with antigens
Pretreatment of T cells
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CTLA-4-/- T cells resist tolerance induction
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How do T cells choose between CD28 and CTLA-4?

• Level of B7 expression on APCs low levels favor
  CTLA-4 engagement (high affinity receptor)
• Kinetics B7 on APCs engages CD28 early, CTLA-4
  late in T cell responses

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Regulation of T cell homeostasis during immune
responses
Anergy
T cell expansion
Magnitude of T cell response
Apoptosis
Activated T cells express CTLA-4
Surviving memory cells
Activated T cells are deprived of antigen and
other stimuli
T cell activation
Time after antigen exposure
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Pathways of apoptosis in T cells
Release of mitochondrial cytochrome
c, activation of caspase-9
Elimination of Antigen and other signals
Passive cell death (death by neglect)
T cell proliferation
Persistence of antigen, repeated stimulation
Fas
Activation induced cell death
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T cell mediated suppression
MBP-TCR In Rag-/-
MBP
MBP-TCR In wildtype
MBP
MBP-TCR In Rag-/-
MBP
CD4CD25 T cells
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Science (2003) 2991057
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• Foxp3 is expressed specifically in TR

• Expression of Foxp3 converts
• naïve CD4 T cells to TR

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Regulatory T cells (TR) in self tolerance

• Phenotype and ontogeny
• CD4cells (most are CD25, some are CD25-) ,
  develop in the thymus
• Recognize self antigens?
• Other populations of regulatory T cells exist
  (including CD8)
• Mechanisms of action
• Antigen-induced suppression secrete
  immunosuppressive cytokines,
• trigger inhibitory cell surface molecules
  (CTLA-4 expressed on TR).
• Prevent the activation of T cells suppress cell
  proliferation and IL-2
• production

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Role of cytokines in suppression of
cell-mediated immune responses
Antigen recognition
T cell proliferation and differentiation
Effector functions of T cells
IL-12
Effector T cells (TH1)
Activated macrophages
Naïve T cell
APC
IFN-?
Cytokines produced by suppressor T cells
IL-10 inhibits Functions of APCs IL-12
secretion, B7 expression
TGF-? inhibits T cell proliferation
IL-4 inhibits action of IFN-?
IL-10, TGF-? inhibit macrophage activation
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Suppressor T cells - unresolved issues

• How many types of suppressor T cells ? cellular
  markers?
• How do they develop ? positive/negative
  selection?
• What are their physiological ligands?
• What are their target cells?
• What is their mechanisms of actions?
• Are they beneficial (for the prevention of
  autoimmunity, allergy and graft rejection)?
• Are they harmful (in terms of their effects on
  tumor immunity, immune response to chronic
  infections and weak vaccines)?

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Conclusions Tolerance vs. Immunity

• Immune responses are the outcome of a balance
  between the need to make a protective response
  and the need to maintain self-tolerance
• Mechanisms of unresponsiveness
• Central tolerance Deletion Receptor editing
• Peripheral tolerance Clonal ignorance Clonal
  deletion Anergy Suppression