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T Cell Activation

What is activation?

increased transcription, translation

cell cycle entry, proliferation

increased ‘help’ for B cells (CD40L, cytokines) + CTL (cytokines)
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increased cell-mediated effector function (granzyme; FasL)
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How are T cells activated in vivo?
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Concept of co-stimulation
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Co-stimulatory molecules, signaling pathways
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Negative regulation of T cell activation
Overview of TCR/CD3
Signaling Pathways
1
3
2
IP3
AP-1
Transcription
Factors
NF-kB
Global changes in transcription upon T cell activation
Gene Induction after Ag recognition
Gene Induction after Ag recognition
Gene Induction after Ag recognition
Dendritic cells sample antigens in peripheral
tissues, mature and migrate to lymph nodes
T Cell
Circulation
Selectin Proteins Help
Direct T Cell Traffic in vivo
Naive T Cells
Integrins also help
direct T cell traffic and
coordinate binding to
different cell types
Strength (Affinity) of
Various Receptor/Ligand Systems
Accessory Molecules
Help Stabilize
T Cell/APC Interactions
‘Immunological synapse’
‘Supra-molecular activation cluster (SMAC)’
“Inside-out” signaling upregulates T cell adhesion to APC
APC Phenotypes
“Two-signal” model of lymphocyte activation
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Burnet - clonal selection hypothesis - B cells (1950s)

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Bretscher and Cohn (1970)

what about hypermutation?

‘helper’ cell (overlapping Ag specif.) for B cell responses
Lafferty and Cunningham (1975)


self-reactive cells must be removed during development
second signal for helper cell (from APC)
Janeway and Medzhitov (~1989-1992)

activation signal for APC (pattern-recog. receptor)

PRR’s bind to conserved structures on pathogens
Roles for Co-Stimulation in T Cell Responses

Increases efficiency of T cell activation
 increases
 signaling
proliferation, cytokine production
effects both quantitative + qualitative

Increases T cell survival

Helps ensure activation by appropriate cells
 i.e.

by cells w/ligands for costim. molecules
professional APC
 particularly
important for naive cells
Co-stimulation +
T cell activation
B Cell activation through
surface Ig is aided by
a co-receptor complex
Molecules with T cell co-stimulatory activity
Mucin
domain
TIM-1
(upregulated)
TIM-4
Yes
Yes
?
?
No
CD28

44 kD surface glycoprotein

Cloned in Brian Seed’s lab (1984)

Later shown to augment T cell proliferation

Also shown to increase IL-2 production


Shown by Allison and colleagues and Jenkins and
Schwartz to prevent anergy in T cell clones
stimulated through TCR alone
Cytoplasmic domain required (signaling)
T Cell Clone Experiments Demonstrating the
Importance of Co-stimulation
Note: No IL-2 produced
IL-2 is a critical growth factor for expansion of effector T
cells and is a target of co-stimulation
Generation of
Effector CTL
w/T Cell Help
Co-Stimulatory Signaling by CD28
CD28 cytoplasmic domain
CD28 - downstream signaling
Some MAPK pathways are targets for
co-stimulatory signals
CD28
NF-kB activation by TCR and CD28
CD28
PI-3K
CARMA1
Akt
Contribution
of CD28 to
NFAT
Activation
Negative Regulation of T Cell Activation
CD28 and CTLA-4



After a T cell becomes activated, it up-regulates
expression of CTLA-4 on the cell surface.
CTLA-4 binds B7 with about 10x higher affinity than
does CD28
This appears to act as a damper on activation
Regulation of CTLA-4 Expression
Lack of CTLA-4 Disrupts Normal T Cell Homeostasis
wild-type
knockout
This suggests that there is
probably some low-level
‘activation’ happening all
the time in vivo, which
CTLA-4 normally dampens
1 cm
Lymphadenopathy
CTLA4-Ig Suppresses Immune Responses
CTLA4-Ig in the clinic:
-autoimmune diseases
Also evidence that CTLA4-Ig binding to
B7 on APC can result in production of
an inhibitory factor (IDO).
CD28 and B7 Family Members
Speculative model for PD-1 Function
Summary

T cell activation is aided by accessory receptors

Activation results in global changes in gene expression


Co-stimulatory molecules are important for activation
and function of T cells
Related inhibitory molecules play a role in limiting
immune responses