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 AP-1 NF-kB 1 3 2 IP3
Transcription
Factors
NF-kB

3. Global changes in transcription upon T cell activation

4. Gene Induction after Ag recognition

5. Gene Induction after Ag recognition

6. Gene Induction after Ag recognition

7. Dendritic cells sample antigens in peripheral tissues, mature and migrate to lymph nodes

8. T Cell
Circulation

9. Selectin Proteins Help Direct T Cell Traffic in vivo
Naive T Cells

10. direct T cell traffic and
Integrins also help
direct T cell traffic and
coordinate binding to
different cell types

11. Strength (Affinity) of Various Receptor/Ligand Systems

12. Help Stabilize T Cell/APC Interactions
Accessory Molecules
Help Stabilize T Cell/APC Interactions
‘Immunological synapse’
‘Supra-molecular activation cluster (SMAC)’

13. “Inside-out” signaling upregulates T cell adhesion to APC

14. APC Phenotypes

15. “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 (~ )
activation signal for APC (pattern-recog. receptor)
PRR’s bind to conserved structures on pathogens

16. 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

17. Co-stimulation + T cell activation

18. B Cell activation through
surface Ig is aided by
a co-receptor complex

19. Molecules with T cell co-stimulatory activity
Mucin
domain
TIM-1
(upregulated)
TIM-4
Yes
Yes ? ? No

20. 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)

21. T Cell Clone Experiments Demonstrating the Importance of Co-stimulation
Note: No IL-2 produced

22. IL-2 is a critical growth factor for expansion of effector T cells and is a target of co-stimulation

23. Generation of Effector CTL w/T Cell Help

24. Co-Stimulatory Signaling by CD28
CD28 cytoplasmic domain

25. CD28 - downstream signaling

26. Some MAPK pathways are targets for co-stimulatory signals
CD28

27. NF-kB activation by TCR and CD28
PI-3K
CARMA1
Akt

28. Contribution of CD28 to NFAT Activation

29. 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

31. Regulation of CTLA-4 Expression

32. 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

33. an inhibitory factor (IDO).
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).

34. CD28 and B7 Family Members

35. Speculative model for PD-1 Function

36. 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