T Cell Activation

Patricia Fitzgerald-BocarslyMarch 18, 2009

Phases of Adaptive Immune Responses

Phases of T cell responses

IL-2 acts as an autocrine growth factor

Fig. 11-11

Clonal Expansion of T cells

• During infection, T cells dramatically expand. • E.g. In EBV infection, Ag specific CTL

represent 0.0001% 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

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

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

Two Competence Signals are Required for Activation of Lymphocytes

Two Competence Signals for T Cells

TLR signaling

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

Gene Expression by Activated T Cells

Fig. 8-6

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 co-stimulation (signal 2)

• Activated T cells are in the periphery and don’t require signal 2

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

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 co-

stimulation. This allows, for example, killing of non-B7 expressing infected cells in the peripheral tissues

CD40:CD40L is another co-stimulatory pair

Fig. 8-5

Cytosolic components transduce signals

• Expression of ITAMs(immunoreceptortyrosine-based activation motif)

Fig. 6-6

T cell receptor signaling leads to complex signaling events

Fig. 8-7

The Immunological Synapse

The Immunological Synapse

Clyclosporin and FK506 act on calcineurin, inhibiting activation of NFAT

Cyclosporin in cardiac transplantation

Fig. 16-8

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

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

Nucleus

JAK1

IFNAR1

IFNAR2

TYK2

STAT1

STAT2

STAT1STAT2

P

P

CytoplasmISRE

IRF9

IFN-induced proteins

IFNβ

Medium

IRF9

GAS

STAT1STAT1

P

P

IFNGR1

IFNGR2

IFNγ

JAK2JAK

1

STAT1

STAT1

IL-28Rα

IL-10R2

TYK2

JAK1

IFNλ

Type I IFNs

Type III IFNs

Type II IFN

With permission from Meager A, and the publisher of The Interferons: Characterization and Application. Copyright Wiley-VCH 2006.

IFN SIGNAL TRANSDUCTION

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 (X-chromosome)