Transcript Presentation

Lecture outline
• Signals for T cell activation
• Costimulation and the B7:CD28
family
– Inhibitory receptors of T cells
• Responses of T cells
• Cytokines
The life history of T lymphocytes
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011
c Elsevier
Principles of lymphocyte activation
• Lymphocytes are normally in a resting
state in lymphoid organs and circulation
• Rapid response to antigen (activation) -->
proliferation, change to functionally active
effector cells (differentiation)
• Migration to tissues, where they perform
their function of eliminating infections
• Multiple possible steps for therapeutic
targeting
Steps in the activation of T lymphocytes
Recognition of antigen by the TCR
The TCR of CD4+ and CD8+
T cells recognizes MHCbound peptide + portions of
the MHC.
Other T cells (gd T cells,
NKT cells) recognize nonpeptide antigens; these are
small cell populations whose
function is unclear.
Antigen recognition by T cells
• Each T cell sees a (self) MHC molecule and a
bound peptide
– Dual recognition determines specificity and
MHC restriction
• Multiple ligands on APCs and receptors on T
cells, in addition to the TCR, participate in
orchestrating responses to antigens
• Signaling: engagement of receptors -->
activation of kinases (often via “adaptor
proteins”) --> activation of transcription
factors
Receptor-ligand pairs involved in
T cell activation
Different molecules involved in T cell responses to
antigen serve distinct functions, seen even in this partial listing.
Drugs that block these ligand-receptor pairs have been developed
to treat immune-mediated inflammatory diseases, graft rejection.
Molecules involved in T cell activation
• Signal transduction
– CD4 and CD8 “co-receptors” recognize MHC
molecules (class II or class I) at the same time
as the TCR sees the peptide-MHC; CD4 and
CD8 provide necessary activating signals for T
cells
– CD28 is a receptor for “costimulators”
expressed on APCs
Molecules involved in T cell activation
•
Signal transduction
– CD4 and CD8 co-receptors recognize MHC molecules (class II
or class I) at the same time as the TCR sees the peptideMHC; CD4 and CD8 provide necessary activating signals for T
cells
– CD28 is a receptor for “costimulators” expressed on APCs
• Strengthen adhesion with antigen-presenting cells
– Integrins function as adhesion molecules
– Affinity of integrins is increased by chemokines produced
during inflammation, and by antigen recognition by TCRs
• Control routes of T cell migration
– Selectins and integrins control migration of naïve T cells
through lymph nodes and of effector and memory T cells
to sites of infection
• Therapeutic targets
Therapeutic targeting of molecules
involved in T cell responses
• CD3: signaling molecule attached to the
TCR on all T cells; anti-CD3 MAb to
deplete T cells (transplants)
• Integrins (LFA-1, VLA-4, others):
adhesion to APCs, endothelium; antiintegrin MAb’s to block leukocyte
migration into tissues
• “Costimulators”: CD28, others;
costimulatory blockade
The two-signal requirement for lymphocyte
activation
Costimulation: signal(s)
in addition to antigen
that are needed to
initiate adaptive immune
responses
Best defined for CD4+ T
cells
Multiple pairs of ligands
on APCs and receptors
on T cells may serve this
function; best defined
are the B7-CD28 families
of proteins
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011
c Elsevier
Role of costimulation in T cell activation
Two signal requirement for T cell activation
• Naïve lymphocytes need two signals to initiate
their responses
• Signal 1: antigen recognition
– Ensures that the response is antigen-specific
• Signal 2: costimulators induced on APCs during
infection (or upon recognition of necrotic cells)
– Ensures that the immune system responds best
to microbes (or to necrotic cells, as in tumors)
and not to harmless antigens
– Adjuvants stimulate expression of costimulators
The B7: CD28 family
Different
members
of the B7CD28
families
serve
different
roles in
stimulating
and
suppressing
immune
responses.
Activation
• B7-CD28: 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
• B7-CTLA-4: inhibits early T cell
responses in lymphoid organs
• PD-1:PD-L1,2: inhibits effector T
cell responses in peripheral tissues
Inhibitory receptors of the immune system
• One mechanism by which the system
maintains a balance between activation and
inhibition is to use different receptors for
different outcomes
• Inhibitory receptors are present in NK cells,
T cells and B cells; other immune cells?
• In many instances, activating receptors work
by recruiting kinases (often via ITAMs) and
inhibitory receptors activate phosphatases
(via ITIMs)
The opposing functions of CD28 and CTLA-4
B7
B7-CD28
interaction APC
CD28
TCR
Naïve
T cell Proliferation,
CTLA-4
B7-CTLA-4
interaction
differentiation
Functional
inactivation
Inhibitory pathways function normally to prevent
responses to self antigens: demonstrated by the
finding that blocking or eliminating these inhibitors
(CTLA-4, PD-1) causes autoimmune disease
Blocking CTLA-4 promotes tumor rejection
Tumor recognition by T cells leads to engagement of CTLA-4 on
the T cells and inhibition of immune responses. Blocking CTLA-4
increases anti-tumor response and leads to tumor rejection.
Inhibitory role of PD-1 in a chronic infection
Virus-specific
T cell response
Residual virus
In a chronic viral infection in mice, recognition of virus by specific T
cells leads to PD-1 engagement, inhibition of T cell responses, and
persistence of the virus. Blocking the PD-1 pathway releases the
inhibition, enhances the T cell response, and leads to viral clearance.
Inhibitory receptors of T cells
• Prevent reactions against self antigens
(their physiologic function)
• Suppress immune responses to some
tumors, chronic infections (HCV, HIV)
• Similar roles are established for both
CTLA-4 and PD-1
The balance between activation and
inhibition
• How does a T cell choose to use CD28 to
be activated or CTLA-4 to shut down?
 Both recognize B7 on APCs
 CTLA-4 (the inhibitory receptor) binds to B7
with much higher affinity than CD28 (the
activating receptor)
The balance between activation and
inhibition
• How does a T cell choose to use CD28 to
be activated or CTLA-4 to shut down?
– Low B7 (e.g. when DC is displaying self
antigen) --> engagement of highaffinity CTLA-4
– High B7 (e.g. after microbe encounter)
--> engagement of lower affinity CD28
• Not well understood for the PD-1
pathway
Therapeutics based on the B7:CD28/CTLA-4 family
1. Costimulatory blockade
CTLA-4.Ig is used for diseases caused by …?
23
Therapeutics based on the B7:CD28/CTLA-4 family
1. Costimulatory blockade
CTLA-4.Ig is being tested in diseases caused by
excessive T cell activation -- rheumatoid arthritis
(FDA approved), psoriasis, graft rejection (approved)
24
Therapeutics based on the B7:CD28/CTLA-4 family
2. Removing the brakes on the immune response
Anti-CTLA-4 antibody is used for ….?
Therapeutics based on the B7:CD28/CTLA-4 family
2. Removing the brakes on the immune response
Anti-CTLA-4 antibody is approved for tumor
immunotherapy (enhancing immune responses against
tumors)
Even more impressive results with anti-PD-1 in
cancer patients
The emerging paradigm for cancer
therapy
• Signaling (e.g. Kinase) inhibitor to block
oncogenic pathways in tumor cells
+
• Immune modulator
– Inhibiting endogenous regulators allows the
host to mount an effective immune response
(let the immune system do the work itself)
– Appears to be more effective than
vaccination and other approaches for
stimulating immunity
– Anti-PD1 may be more effective than antiCTLA-4 (less toxic, greater effect on CTLs)
27
Costimulation
• Required for initiating T cell responses
– Many proteins on APCs and their receptors on T cells
shown to “costimulate” (function with antigen to
activate T cells); most important costimulators are
B7:CD28
• Ensures that T cells respond to microbes (the
inducers of costimulators) and not to harmless
antigens
– Source of costimulation in responses to tumors and
transplants: products of dead cells?
• Therapeutic targets
T cell expansion and contraction (decline)
Many aspects of T cell responses and functions are mediated
by cytokines: initial activation -- IL-2; maintenance of
memory cells -- IL-7; effector functions -- various
Cytokines
• Secreted proteins that mediate immune and
inflammatory reactions, and communications
among leukocytes and other cells
• Produced transiently in response to extrinsic
stimuli
• Bind to high-affinity receptors on target cells
• Actions are most often autocrine and paracrine,
rarely endocrine
• Cytokines are pleiotropic (one cytokine has
multiple actions) and redundant (different
cytokines have similar actions)
Role of IL-2 and IL-2 receptors in T cell proliferation
Production of IL-2 and expression of high-affinity IL-2 receptors
are both dependent on antigen recognition + costimulation
Clonal expansion (proliferation) of T cells
• Stimulated mainly by autocrine IL-2
– T cell stimulation by antigen + costimulators
induces secretion of IL-2 and expression of highaffinity IL-2 receptors
– Therefore, antigen-stimulated T cells are the
ones that expand preferentially in any immune
response, keeping pace with replicating microbes
Clonal expansion (proliferation) of T cells
•
Stimulated mainly by autocrine IL-2
– T cell stimulation by antigen + costimulators induces secretion of
IL-2 and expression of high-affinity IL-2 receptors
– Therefore, antigen-stimulated T cells are the ones that expand
preferentially in any immune response, keeping pace with
replicating microbes
• CD8+ T cells may expand >50,000-fold within a
week after an acute viral infection with minimal
expansion of cells not specific for the virus (up to
10% of all CD8+ T cells in the blood may be
specific for the pathogen)
• Some of the progeny of the expanded clone
differentiate into effector and memory cells; the
majority die by apoptosis
Naïve T cells differentiate into functional
effector cells
Effector T cells
CD4+ helper
T cells
Naïve T cell:
Can recognize
antigen but
incapable of any
functions
Differentiation
APC
+ antigen
+ antigen
Cytokine
secretion
CD8+ CTLs
Cell
killing
Memory T cells
• Long-lived, functionally silent
– More numerous than naïve cells specific for the antigen;
respond more rapidly than do naïve cells -- explains why
secondary response is “better” than primary response
• May consist of multiple subsets
– Some migrate to lymphoid organs (like naïve T cells), and
proliferate and differentiate rapidly in response to antigen
challenge (repeat infection)
– Others migrate to peripheral sites of infection, and
rapidly perform effector functions upon encountering the
antigen
The life history of T lymphocytes
Precursors mature in the thymus
Naïve CD4+ and CD8+ T cells enter the circulation
Naïve T cells circulate through lymph nodes
and find antigens
Clonal expansion;
differentiation into effector and memory cells
Effector T cells migrate to sites of infection
Eradication of infection