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T Cell Maturation and Activation February 15, 2001 Outline T Cell Maturation Early development in the thymus Positive Selection and Negative Selection CD4 + T Cells vs. CD8 + T Cells T Cell Activation Signal Transduction/Gene Expression Costimulation Expansion vs. Anergy

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T Cell Maturation and Activation

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T Cell Maturation and Activation

February 15, 2001


Outline

  • T Cell Maturation

    • Early development in the thymus

    • Positive Selection and Negative Selection

    • CD4+ T Cells vs. CD8+ T Cells

  • T Cell Activation

    • Signal Transduction/Gene Expression

    • Costimulation

    • Expansion vs. Anergy


T Cell Maturation

(Bone Marrow  Thymus  Periphery)


Fig. 10-2


Fig. 10-3


Fig. 10-5

Positive Selection

And

Negative Selection


Fig. 10-6

Positive Selection


Positive Selection


Fig. 10-8

Negative Selection


A Paradox…..

  • Positive Selection – Allows survival of thymocytes which recognize self-MHC. Other thymocytes die by apoptosis. ( Self-MHC restriction)

  • Negative Selection – Leads to apoptosis of thymocytes with high avidity for self-MHC, or with an avidity for self-MHC + self-Ag. ( Self Tolerance)

    Positive Selection  Negative Selection  No T Cells?

  • Clearly, not all thymocytes are deleted by apoptosis during negative selection, or we would not have any T cells.


Two Hypotheses…..

  • Avidity Hypothesis – High-avidity binding of TCR to MHC/Ag leads to apoptosis, but low-avidity binding leads to release from the thymus of mature T cells.

  • Differential Signaling Hypothesis – “Complete” signals through TCR by MHC/Ag lead to apoptosis, but “weak or partial” signals lead to release from the thymus of mature T cells.

  • Experimental data support some combination of both hypotheses


Fig. 10-9

CD4+ T Cells vs. CD8+ T Cells - 2 Models...


Outline

  • T Cell Maturation

    • Early development in the thymus

    • Positive Selection and Negative Selection

    • CD4+ T Cells vs. CD8+ T Cells

  • T Cell Activation

    • Signal Transduction/Gene Expression

    • Costimulation

    • Expansion vs. Anergy


T Cell Activation

  • Interaction of TCR/CD3 complex with MHC/Ag complex leads to activation signal(s)

  • This interaction also involves accessory or costimulatory molecules

  • Activation signals cause T cells to enter cell cycle

  • This involves activation of numerous genes


Signal Transduction

  • Receptor-Ligand Interactions

  • Second Messengers (cAMP, Ca2+, DAG, IP3)

  • Protein Kinases, Protein Phosphatases

  • G Proteins (GTP-binding proteins)


Fig. 10-12


Fig. 10-14

Costimulation


Clonal Expansion vs. Clonal Anergy

  • Clonal Expansion - Expansion/proliferation of a clone of T cells from a single, activated T cell

  • Clonal Anergy - Inactivation of a T cell

  • Interaction of TCR/CD3 with MHC/Ag can result in either expansion or anergy

  • This outcome is dependent on costimulation (w/costimulation  expansion; w/out costimulation  anergy)


Fig. 10-15


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