Transcript Peripheral tolerance in B cells (II): Anergy

Immune Regulation
and
Tolerance
Immunoregulation: A balance between activation and
suppression of effector cells to achieve an efficient
immune response without damaging the host.
Activation (immunity)
autoimmunity
Suppression (tolerance)
immunodeficiency
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.
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
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)
Mechanisms of unresponsiveness:
Central tolerance in B and T cells (I): Clonal Deletion
Self antigen
presented in
generative
lymphoid
organs
Lymphoid
precursor
Deletion of
immature
lymphocytes
strongly recognizing
self antigens
present in
generative organs
Survival of clones which
are only moderately
responsive to self antigens
present in generative
organs; forms T cell
repertoire
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.
aire -/-
WT
Mechanisms of unresponsiveness:
Central tolerance in B cells (II):Receptor editing
bone
marrow
pre-B

rearrangement
further
rearrangement
immature
B
10%
B
Maturation of clones:
• Non-reactive to soluble• low-affinity to soluble•self-reactive to
monovalentantigens in bone marrow
B follicle
T cell 2%
zone
B220
Moma-1
Spleen
artery
TCR
Self
antigens
90%
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?)
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.
Mechanisms of unresponsiveness:
Peripheral tolerance in B cells (II): Anergy
Immunogenic signaling
Acute
antigens
Tolerogenic signaling
Chronic
antigens
CD40L
LPS
CD40
CD40
TLR4
BCR
BCR
Ca++
NFB
Growth genes
TLR4
Fcg2b
Ca++
NFB
Inhibitory genes
Anergic B cells can respond to “Stronger” antigens
Oligovalent self antigens
Constitutively exposed
Multivalent foreign antigens
Acutely exposed
Anergic
B cell
Anergic
B cell
Remains anergic
Activated
The two-signal requirement for T cell activation
TCR
Microbial antigen
presented by APC
MHC
Signal 1
APC
Signal 2
Costimulatory
Receptor (CD28)
B7
The role of co-stimulation in T cell activation
Antigen recognition
T cell response
CD28
Resting APC:
(costimulatordeficient)
No response
Activation of APC
Innate immune response
Activated APC:
increased
expression of
costimulators,
secretion of
cytokines
B7 CD28
T cell proliferation
And differentiation
Two-signal requirement for T lymphocyte
activation
 Naïve T lympho cytes need two signals
to initiate responses
 Signal 1: antigen recognition
 Ensure that the immune response
is antigen- specific
 Signal 2: microbes or substances
produced dur ing inna te immune
responses to microbes
 Ensure that the immune sy stem
responds to microbes and no t to
harmless antigenic substance
(Second signals for T cells are
costimulators on APCs and cytokines
produced by APCs.)
Mechanisms of unresponsiveness:
Peripheral tolerance in T cells (II): Anergy
Pretreatment
of T cells
Stimulation
with antigens
B7 CD28
CD28
18-24 hr
B7 CD28
B7 CD28
18-24 hr
T cell
response
Molecular basis of anergy in T lymphocytes
TCR
CD3z
P
Zap 70
GROWTH
FACTORS
CELL
CYCLE
PROXIMAL
EVENTS:
- Reduced tyrosine
phosphorylation
- Reduced Ca++ influx
NUCLEAR EVENTS:
- no induction of NFB
JNK activities
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
Mechanisms of unresponsiveness:
Peripheral tolerance in T cells (II): Anergy
Pretreatment
of T cells
Stimulation
with antigens
B7 CD28
T cell
response
B7 CD28
18-24 hr
primed
B7 CD28
CD28
18-24 hr
tolerated
CTLA-4-/- T cells resist tolerance induction
Primed
Tolerated
Days
How do T cells choose between CD28 and CTLA-4?
• Level of B7 expression on APCs: low levels favor CTLA4 engagement (high affinity receptor)
• Kinetics: B7 on APCs engages CD28 early, CTLA-4 late
in T cell responses
Magnitude of T cell response
Regulation of T cell homeostasis during immune responses
T cell
expansion
Anergy
B7 CTLA-4
Activated T cells
express CTLA-4
B7
Apoptosis
CD28
Activated T cells are
deprived of antigen
and other stimuli
T cell
activation
Time after antigen exposure
Surviving
memory cells
Pathways of apoptosis in T cells
Release of
mitochondrial
cytochrome c,
activation of
caspase-9
Elimination
of Antigen and
other signals
B7
CD28
“Passive”
cell death
(death by
neglect)
T cell proliferation
IL-2
Persistence
of antigen,
repeated
stimulation
Fas
FasL
Activation of
caspase-8
Activation
induced
cell death
T cell mediated suppression
MBP-TCR
In Rag-/-
MBP
MBP-TCR
In wildtype
MBP
MBP-TCR
In Rag-/-
MBP
CD4+CD25+ T cells
Science (2003) 299:1057
• Foxp3 is expressed specifically in TR
• Expression of Foxp3 converts
naïve CD4+ T cells to TR
Regulatory T cells (TR) in self tolerance
• Phenotype and ontogeny:
CD4+cells (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
Role of cytokines in suppression
of cell-mediated immune responses
Antigen
recognition
T cell proliferation
and differentiation
IL-12
APC
Cytokines
produced by
suppressor
T cells
Naïve T cell
IL-10 inhibits
Functions of APCs:
IL-12 secretion, B7
expression
Effector functions
of T cells
Effector T cells
(TH1)
IFN-g
TGF- inhibits
T cell
proliferation
Suppressor T cells
Activated
macrophages
IL-4 inhibits
action of
IFN-g
IL-10, TGF-
inhibit
macrophage
activation
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)?
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