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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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Presentation Transcript
outline
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
slide3

T Cell Maturation

(Bone Marrow  Thymus  Periphery)

slide6

Fig. 10-5

Positive Selection

And

Negative Selection

slide8

Fig. 10-6

Positive Selection

slide10

Fig. 10-8

Negative Selection

a paradox
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
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
slide13

Fig. 10-9

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

outline14
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
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
Signal Transduction
  • Receptor-Ligand Interactions
  • Second Messengers (cAMP, Ca2+, DAG, IP3)
  • Protein Kinases, Protein Phosphatases
  • G Proteins (GTP-binding proteins)
slide19

Fig. 10-14

Costimulation

clonal expansion vs clonal anergy
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)