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T Cell Activation. Costimulation, Inhibition, and the Immunologic Synapse. Immunology’s “Dirty Little Secret”. Early experiments demonstrated that antigen-derived (i.e. TCR-mediated) signals alone are insufficient to initiate an immune response

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T Cell Activation


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t cell activation

T Cell Activation

Costimulation, Inhibition, and the Immunologic Synapse

slide2

Immunology’s “Dirty Little Secret”

Early experiments demonstrated that antigen-derived (i.e. TCR-mediated) signals alone are insufficient to initiate an immune response

A second substance - an “adjuvant” - is required to prevent the induction of tolerance

In vitro, triggering the TCR alone also leads to a tolerant state (known as “anergy”)

“Two-Signal Hypothesis”: Activation of a naïve T cell requires signals from both the TCR (antigen-specific) and a second, co-stimulatory receptor (antigen-independent)

Adjuvants work in part by inducing antigen presenting cells to express ligands for co-stimulatory receptors

slide4

CD28: The First (and still the champ!) Co-stimulatory Molecule

Yet another member of the immunoglobulin superfamily (single Ig-V domain)

Expressed on the surface of almost all T cells (100% of mouse T cells, ~80% of human T cells) as a disulfide-linked dimer

Binds to B7-1 (CD80) and B7-2 (CD86) expressed on antigen presenting cells

Cytoplasmic tail has binding motifs for several signaling molecules (PI3K, Grb2, Itk), but no ITAM. It is still unclear what signals CD28 contributes to T cell activation

Signaling by CD28 alone does not stimulate T cells, and only activates PI3K

slide5

CTLA-4: Putting on the Brakes

CTLA-4 is another CD28-related receptor, and binds both B7-1 and B7-2 - avidity is at least 20x as high as CD28

CTLA-4 expression on the surface is undetectable in resting T cells, but is rapidly increased after TCR + CD28 signaling

Unlike CD28, CTLA-4 is inhibitory, and blocks T cell proliferation and IL-2 production - combination of competing B7 molecules away from CD28 and bona fide inhibitory signals (possibly phosphatases, but still not well defined)

slide6

Fig. 8.12 T-cell activation through the T-cell receptor and CD28 leads to the increased expression of CTLA-4, an inhibitory receptor for B7 molecules.

slide7

Polarization of T Cells Part I: The Cytoskeleton

  • T cell responses are directed at the APC/target cell, not in all directions
  • This requires reorganization of the cell to have a “front” (toward the APC) and a “back” - induced by signals from the TCR and costimulatory molecules
  • Result: Reorganization of the cytoskeleton causes reorientation of cytosolic organelles toward APC - Golgi, secretory vessicles, and microtubule organizing center (MTOC). The MTOC connects actin cytoskeletal changes with the tubulin cytoskeleton
slide9

Polarization of T Cells Part II: Lipid Rafts

Lipid rafts - also called GEMs (glycolipid enriched microdomains) and DIGs (detergent-insoluble glycolipid-rich domains) - are plasma membrane microdomains

Enriched in cholesterol, glycolipids, and sphingolipids (i.e. lipids that are not glycerol-based), making them more rigid than the surrounding membrane

Some membrane proteins are segregated - selectively enriched or depleted in rafts. Many key signaling molecules (esp. src-family kinases) are constitutively localized to lipid rafts.

Dynamic structures - small rafts can condense to form larger rafts

During T cell activation, TCR, CD28, and many adhesion molecules are recruited into lipid rafts, where they can interact with signaling molecules

slide12

The Immunologic Synapse - Putting it Together

The combination of cytoskeletal rearrangement and lipid raft redistribution leads to the formation of a Supramolecular Activation Complex (SMAC) - a highly ordered arrangement of receptors, adhesion molecules, and signaling molecules

slide13

Effector T Cell Functions:

CTL

Th1/Th2

Regulatory T Cells

Peripheral Tolerance

Abbas Chapters 10, 13

t cell subsets
T Cell Subsets
  • CD8/CTL
  • CD4/TH cells

1) TH1 - inflammatory response

2) TH2 - anti-inflammatory, B cell response

3) Treg - inhibit immune responses

slide15

The main function of CD8+ cells is to differentiate into CTL, which kill pathogen-infected cells

mechanisms of cytotoxicity
Mechanisms of Cytotoxicity
  • CTL (but not naïve CD8+ T cells) express lytic granules: perforin, granzymes, granulysin
  • Perforin lysis of target cell (inefficient)
  • Granzyme activation of cytosolic apoptosis machinery
  • Fas/FasL induction of apoptosis
cd4 subsets t h 1 vs t h 2
CD4+ Subsets: TH1 vs. TH2
  • Highly investigated in mouse model of leishmaniasis: C57BL/6 mouse cures, but Balb/c mouse dies of uncontrolled infection
  • Strains differ in cytokine responses
  • Resistant mice produce interferon-g (IFN-g), tumor necrosis factor-a (TNF-a), and lymphotoxin, which activate inflammatory response and cell-mediated immunity: TH1
  • Susceptible mice produce interleukin (IL)- 4, 5, 13, which are anti-inflammatory and promote B cell activation and antibody production: TH2
slide19

Leishmania infection in mice

BALB/c (Th2)

Lesion size (mm)

BALB/c + IL-12

C57Bl/6 (Th1)

Days

t h 1 vs t h 2 differentiation depends on cytokine milieu
TH1 vs. TH2 Differentiation Depends on Cytokine Milieu
  • TH1 differentiation is driven by the APC-derived cytokine IL-12
  • TH2 differentiation is driven by the T cell-derived cytokine IL-4
  • IL-12 and IL-4 are mutually antagonisitic: IL-12/IFN-g inhibit IL-4 secretion and vice versa, leading to strongly polarized response
slide24

Th2

Additional Figures

regulatory t cells
Regulatory T Cells
  • Long and spotty history of study: “suppressor” cells, “veto” cells, “infectious tolerance”, and now “regulatory” T cells
  • Basic premise: one or more populations of T cells act to inhibit the responses of other T cells
regulatory t cells cont
Regulatory T Cells cont.
  • Sakaguchi and colleagues found that thymectomy in <3 day-old mouse results in multiorgan autoimmunity
  • Identified population of CD4+CD25+ T cells that restore self-tolerance
  • Differentiation into Treg requires expression of FoxP3 (scurfin)
  • Suppression of responses by both contact-dependent (inhibition of APC) and cytokine (IL-10, TGF-b) mechanisms
mechanisms of peripheral t cell tolerance
Mechanisms of Peripheral T Cell Tolerance
  • Clonal Deletion (apoptosis)

1) Activation-induced cell death (Fas/FasL)

2) “Veto” cells (CD8+; TRAIL/TRAIL-R)

  • T Cell Anergy

1) TCR signal w/o costimulation?

2) TCR signal + CTLA-4?

  • Active suppression (Treg)