T Cell Maturation and Activation

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T Cell Maturation and Activation

• February 15, 2001

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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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Positive Selection And Negative Selection
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Positive Selection
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Positive Selection
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Negative Selection
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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.

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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

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

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Signal Transduction

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

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Costimulation
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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)

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