T Cell Activation

1
T Cell Activation

• What is activation?
• increased transcription, translation
• cell cycle entry, proliferation
• increased help for B cells (CD40L, cytokines)
  CTL (cytokines)
• increased cell-mediated effector function
  (granzyme FasL)
• How are T cells activated in vivo?
• Concept of co-stimulation
• Co-stimulatory molecules, signaling pathways
• Negative regulation of T cell activation

2
Overview of TCR/CD3 Signaling Pathways
1
3
2
IP3
AP-1
Transcription Factors
NF-kB
3
Global changes in transcription upon T cell
activation
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Gene Induction after Ag recognition
5
Gene Induction after Ag recognition
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Gene Induction after Ag recognition
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T cell trafficking and activation by APCs
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Dendritic cells sample antigens in peripheral
tissues, mature and migrate to lymph nodes
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T Cell Circulation
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Selectin Proteins Help Direct T Cell Traffic in
vivo
Naive T Cells
11
Integrins also help direct T cell traffic
and coordinate binding to different cell types
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Accessory and Co-Stimulatory Moleculesin T Cell
Activation
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Strength (Affinity) of Various Receptor/Ligand
Systems
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Accessory Molecules Help Stabilize T Cell/APC
Interactions
Immunological synapse Supra-molecular
activation cluster (SMAC)
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Inside-out signaling upregulates T cell
adhesion to APC
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APC Phenotypes
17
Two-signal model of lymphocyte activation

• Burnet - clonal selection hypothesis - B cells
  (1950s)
• self-reactive cells must be removed during
  development
• Bretscher and Cohn (1970)
• what about hypermutation?
• helper cell (overlapping Ag specif.) for B cell
  responses
• Lafferty and Cunningham (1975)
• second signal for helper cell (from APC)
• Janeway and Medzhitov (1989-1992)
• activation signal for APC (pattern-recog.
  receptor)
• PRRs bind to conserved structures on pathogens

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Roles for Co-Stimulation in T Cell Responses

• Increases efficiency of T cell activation
• increases proliferation, cytokine production
• signaling 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

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Co-stimulation T cell activation
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B Cell activation through surface Ig is aided
by a co-receptor complex
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Molecules with T cell co-stimulatory activity
Mucin domain
TIM-1 (upregulated)
TIM-4
Yes
Yes
?
?
No
22
CD28

• 44 kD surface glycoprotein
• Cloned in Brian Seeds 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)

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T Cell Clone Experiments Demonstrating the
Importance of Co-stimulation
Note No IL-2 produced
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Co-stimulation Can Be Provided In Trans
Fixed APC untreated APC Fixed APC
anti-CD28 Ab
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Function of IL-2 in T Cell Priming/Expansion
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IL-2 is a critical growth factor for expansion of
effector T cells and is a target of co-stimulation
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Generation of Effector CTL w/T Cell Help
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CD28 Signaling
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CD28 cytoplasmic domain
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CD28 - downstream signaling
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Some MAPK pathways are targets for
co-stimulatory signals
CD28
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NF-kB activation by TCR and CD28
CD28
PI-3K
CARMA1
Akt
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Contribution of CD28 to NFAT Activation
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Negative Regulation of T Cell Activation
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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

36
(No Transcript)
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Regulation of CTLA-4 Expression
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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
39
CTLA4-Ig Suppresses Immune Responses
CTLA4-Ig in the clinic -transplants -autoimmune
diseases
Also evidence that CTLA4-Ig binding to B7 on APC
can result in production of an inhibitory factor
(IDO).
40
CD28 and B7 Family Members
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Speculative model for PD-1 Function
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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