T Cell Activation. Patricia Fitzgerald-Bocarsly March 18, 2009

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1 T Cell Activation Patricia Fitzgerald-Bocarsly March 18, 2009

2 Phases of Adaptive Immune Responses

3 Phases of T cell responses

4 IL-2 acts as an autocrine growth factor Fig

5 Clonal Expansion of T cells During infection, T cells dramatically expand. E.g. In EBV infection, Ag specific CTL represent % of the resting (naïve) T cells, but during active infection, can be as many as 10% After expansion, Ag specific CD4 may be 1% of the T helper pool T cell division begins within 18 hours after activation and each cycle takes about 6 hr

6 Effector phase During the effector phase, the expanded T cells carry out their functions Th: help for antibody production, macrophage activation Cytotoxic T cells: kill virally-infected cells

7 Resolution of infection and establishment of memory After resolution of infection, these antigen-activated cells are unnecessary and die by apoptosis Some of the cells become Ag-specific memory cells, which can represent 0.01% of the circulating T cells

8 Two Competence Signals are Required for Activation of Lymphocytes

9 Two Competence Signals for T Cells TLR signaling

10 Gene expression following TcR ligation Immediate genes: expressed within half an hour. Transcription factors: c-fos, c- Myc, c-jun, NFAT and NK-κB Early Genes: 1-2 hr; IL-2, IL-2R, IL-3, IL-6, IFN-γ Late genes: >2 days; adhesion molecules

11 Gene Expression by Activated T Cells Fig. 8-6

12 Activation of Naïve vs. Activated T Cells Naïve T cells have a higher threshold of activation than activated T cells Naïve T cells are primarily activated in lymphoid organs by DC DC deliver both MHC-Ag (signal 1) and costimulation (signal 2) Activated T cells are in the periphery and don t require signal 2

13 Why Co-Stimulation? Innate signaling (often through TLR) upregulates B7 on APC B7 (CD80 and CD86) on APC interacts with CD28 on the T cell Failure to co-stimulate leads to anergy - prevents unnecessary T cell activation Genes have CD28 response elements

14 Co-stimulation (cont.) Co-stimulation leads to upregulation of IL-2 production (among others), leading to 100- fold more IL-2 to activate the naïve T cells Increased transcription of IL-2 gene Increased stability of transcript Anti-apoptotic signals so that T cells survive Once activated, T cells don t require costimulation. This allows, for example, killing of non-b7 expressing infected cells in the peripheral tissues

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20 CD40:CD40L is another costimulatory pair Fig. 8-5

21 Cytosolic components transduce Expression of ITAMs (immunoreceptor tyrosine-based activation motif) signals Fig. 6-6

22 T cell receptor signaling leads to complex signaling events Fig. 8-7

23 The Immunological Synapse

24 The Immunological Synapse

25 Clyclosporin and FK506 act on calcineurin, inhibiting activation of NFAT

26 Cyclosporin in cardiac transplantation Fig. 16-8

27 Activation Defects in Human Immunodeficiency ZAP-70 tyrosine kinase deficiency: a type of SCID Bruton s (X-linked) agammaglobulinemia: caused by a defect in Btk X-linked hyper-igm: mutation in CD40L on T cells

28 Cytokine Signaling Cytokines bind to their receptors on the cell surface Transduce signals (e.g. through JAK/STAT pathway) Results in induction of genes with appropriate response elements - a single cytokine can turn on multiple genes, and different cytokines may turn on the same genes - pleiotropic and redundant Deficiency in cytokine signaling can lead to immunodeficiency

29 Type III IFNs IL-28Rα IFNλ IFN SIGNAL TRANSDUCTION Type I IFNs IFNβ IFNAR2 IFNAR1 IFN-induced proteins TYK2 STAT1 JAK1 JAK1 STAT2 IRF9 TYK2 P STAT1 STAT2 IRF9 P ISRE IL-10R2 STAT1 GAS JAK1 P STAT1 STAT1 P IFNGR1 JAK2 STAT1 IFNγ IFNGR2 Cytoplasm Type II IFN Medium Nucleus With permission from Meager A, and the publisher of The Interferons: Characterization and Application. Copyright Wiley-VCH 2006.

30 IL-2R gamma chain deficiency IL-2R gamma chain is shared by IL-2, 4, 7, 9, 15, 21 and 27 receptors Lack of gamma chain leads to defective signaling through these receptors IL-7 is needed for lymphocyte development This deficiency therefore results in X- linked SCID (Xchromosome)