T-Cell Maturation, Activation, and Differentiation

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T-Cell Maturation, Activation, and Differentiation

• By
• Stew Chris

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Overview

• Early Development
• T-Cell Repertoire Selection Processes
• Late Development
• Activation
• Differentiation
• Cell Death

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Early Development

• What is required for maturation in the thymus?
• Experiment by J.C. Zuniga Pfluker
• Gene knockout on mice
• T Cells can develop in the absence of thymic
  fragments
• Notch1 ligand required for T-cell precursor to
  form

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Developmental Steps in the Thymus

• Cell-Surface Molecules
• c-Kit Receptor for stem cell growith factor
• CD44 Adhesion Molecule
• CD25 Alpha-Chain of the IL-2 receptor

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T-Cell Development

• T-Cell precursor in Double Negative State
• DN1 DN4 ? changes in cell-surface protein
  expression
• DN2 is a crucial state
• RAG expression ? gene rearrangements
• Determination of Beta Chain of TCR
• CD3 gene is expressed

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TCR is now in the Double Positive (DP) State
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Thymic Selection Processes

• Thymocytes are in the Double Positive State (i.e.
  express both coreceptors.
• Positive and Negative Selection necessary to
  produce an effective T-Cell repertoire.

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Positive Selection

• Results in MHC restriction
• Mechanism
• Immature thymocytes cluster with MHC molecules on
  the cortical cells of the thymus
• If TCR interacts with MHC ? protective signal
  results that prevents apoptosis.
• If TCR does not interact with MHC ? no protective
  signal and apoptosis occurs.
• Result? Only reactive thymocytes survive.

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Negative Selection

• Ensures self-tolerance
• Weeds out High affinity thymocytes
• Mechanism
• APCs bearing MHCs interact with thymocytes
• If avidity is too strong ? thymocyte undergoes
  apoptosis.
• Details unknown
• Result? Only self-tolerant thymocytes survive.

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Positive Selection Experiment

• Thymocytes are dependent on the presence of MHCs
  in the thymus for survival.
• Class I MHC knockout ? CD4 is selected for, but
  CD8 does not survive.
• Class II MHC knockout ? CD8 is selected for, but
  CD4 does not survive.

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Negative Selection Experiment

• H-Y peptide expressed form Y Chromosome (only in
  males)
• T-cells against the H-Y peptide are found only in
  females!!!
• Why?
• Male cell recognizes H-Y peptide as a
  self-pathogen ? T-cells against H-Y peptide are
  negatively selected and eliminated.

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Unresolved Thymic Issues

• How do thymocytes survive selection processes???
• Avidity Hypothesis - Strength of signal
• Differential-Signaling Hypothesis
• ??????????????????????????????????

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Thymocyte Activation

• TCR complex binds MHC ligand and signal is
  transduced
• Cell cycle
• Proliferation
• differentiation

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Costimulatory Signal
CD28 B7 Activation of TF for IL-2
Antagonists
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Cell Death!

• How does apoptosis occur during thymocyte
  selection??
• Specialized Protease called Caspases
• Every cell produces these proteases which are
  maintained in an inactive form
• Must activate to undergo apoptosis

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Death Signal!!!
2 Pathways