T cell Activation

Describe Naive T cell activation:

• Location

• What are Lymphnodes

• List the locations of activation by type of infection

Naïve T cell activation

• Location:

  • secondary lymphoid tissues;

    • APCs present Ag

• Lymph nodes:

  • draining an infected or inflamed area is a depot of processed antigen on DCs and macrophages (MØ).

• Types/Locations

  • blood infections:

    • activation occurs in spleen.

  • respiratory infections:

    • activation occurs in

      • adenoids,

      • tonsils,

      • other bronchial-associated lymphoid tissues.

  • GI infections:

    • Peyer’s patches,

    • other gut-associated lymphoid tissues.

Describe the mechanism for lymphocyte homing

• Definition?

• Mech

Lymphocyte Homing:

• Definition:

  • movement of naïve T cells into secondary lymphoid tissues.

• Mechanism:

  • Rolling:

    • weak interaction between naïve T cells and endothelial cells in lymph node HEV

      • L-selectin (T) - CD34 and GlyCAM-1 (HEV)

    • Slows down flow of circulating lymphocytes

  • LFA Activation:

    • CCL21 (HEV) - CCR7 (T)

  • Diepedesis

    • Activated LFA-1 binds ICAM1

1. List the adhesion molecules involved in T cell-APC interactions

   • Initial Transient

   • Strong Adhesion

2. Describe the mechanism for LFA activation

Adhesion Molecules:

• Initial Transient binding:

  • mediated by integrins and members of Ig superfamily.

  • LFA1 (T) - ICAM-1/2 (APC)

• Strong Adhesion:

  • CD2 (T) - LFA-3 (APC)

  • ICAM-3 (T) - DC-SIGN (APCs)

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LFA activation

• Initial T-APC binding → T cell samples peptide: MHC complex (APCs) → induce conformational change on LFA-1 → stronger binding to ICAMs

  • more stabilized interaction that last several days

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NOTE: LFA: Lymphocyte function-associated antigen, ICAM: Intercellular adhesion molecule

DC-SIGN: DC-specific ICAM-3 grabbing non integrin

Describe Initial T-Cell Activation

• Describe the Binding/ Signaling pathway/ and effect of Signal 1 and 2

• Describe the Binding and effects of Signal 3

Activation Signals 1 and 2:

• 1:

  • Binding:

    • TCR complex + CD4/8 (T) - Peptide on MHC (APC)

  • Signaling Pathway:

    • Src family kinases → phosphorylate TCR ITAMs ((Immunoreceptor Tyrosine Activating Motif)) → downstream effects

• 2:

  • Binding:

    • Int. btw co-stimulatory molecules

    • CD28 (T) - B7.1 (CD80) or B7.2 (CD86) (APC)

  • Signaling Pathway:

    • Zap-70 → phosphorylates adaptors → continues cascade

• Effect of 1 and 2:

  • activates NFAT, NK-kB, AP-1, Protein synthesis

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Activation Signals 3:

• Binding:

  • Cytokines (APCs/other immunes cells) - T Cells

    • IL-6

    • IL-12

    • TGF-B

• Effect:

  • influences subsequent effector function of CD4+

    • Cytokine Composition dependent

  • induce CD8+ T cell → CTLs (cytotoxic T lymphocytes)

  • Induction of Adaptive Immunity

What happens when Signals 1 or 2 are Missing?

• W/O signal 1:

  • No effect on T cells

• W/O signal 2:

  • T cell becomes anergic

1. What does TCR activation leads to?

2. Describe the main effect of immunosuppressive drugs; List them and their function

TCR Activation

• → IL-2 production + expression of High-Affinity IL2R (has alpha chain now) → T Cell Proliferation

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Immunosuppressive Drugs:

• Main Effect: block unwanted expansion of T cells:

• List/Function:

  • Cyclosporin A + Tacrolimus (FK506)

    • disrupts TCR signaling.

  • Rapamycin

    • inhibits signaling downstream of the IL2R.

Describe superantigens:

• Mech

• Effect

superantigens

• Mechanism:

  • binds both MHC protein + TCR together (@ positions outside the normal binding site (

• Effect:

  • stimulates massive

    • T-cell activation,

    • cytokine release

    • systemic inflammation