T cell differentiation

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Development of CD4+ T-Cell Subpopulations

• Within the blood and lymphoid organs the majority of CD4+ T cells are antigen-naive T-cells.
  • There is only a small proportion of memory T-cells.
• Naive T-cells have yet to encounter antigen.
  • can only be activated by antigen presented by dendritic cells.
• After initial antigenic activation, naïve T-cells develop into an intermediate stage cell.
  • The TH₀ cell.
  • Can then be activated by any antigen-presenting cell.
    • Dendritic cell, macrophage or B-cell.
• The TH₀ cells have the capacity to differentiate into TH₁ and TH₂ cells.
  • The type of cell that develops depends on the antigen presenting cell.
    • Macrophages cause the TH₀ cell to develop into TH₁ cells.
      • Caused by IL-12 production following macrophage-antigen interaction.
    • B-cells cause the TH₀ cell to develop into TH₂ cells.
      • Caused by IL-10 production following B-cell-antigen interaction,
• On antigenic stimulation the TH₁ or TH₂ cells become activated.
  • Undergo clonal expansion and secrete a range of different cytokines.
    • For any one cell the cytokine-secreting activation state is short-lived.
      • 4 - 40 hours.
      • After this time these cells either:
        • Die, or
        • Mature into the long-lived memory cells.
• The proliferation of T cells continues until antigen disappears.

TH₁ Cells

• TH₁ cells secrete a range of cytokines.
• Cytokines secreted include:
  • IL-2.
    • Gives proliferation of both CD4+ and CD8+ T-cells.
    • This stimulation of proliferation of T-cells is the main function of the TH₁ cell.
  • Interferon gamma (IFNγ).
    • Activates tissue macrophages
    • Is the principal effector mechanism in the defence against intracellular bacteria and parasites.
      • E.g. Mycobacteria, Brucella, Rickettsia (bacteria) and Leishmania, Coccidia, Babesia (parasites).
      • Activates macrophages and stimulates them to produce enzymes triggering the intracellular killing mechanisms, e.g.
        • Superoxide dismutase and myeloperoxidase.
          • Produce H₂O₂ and trigger the "superoxide burst".
        • Nitric oxide synthase.
          • Produces nitric oxide.
      • This is another example of the immune system working through the innate immune response.
    • Can act to suppress antibody synthesis.

TH₂ Cells

• The TH2 population influences B-cell activation, proliferation and immunoglobulin production.
• The TH2 T cell population secrete a range of cytokines.
  • IL-4
    • Stimulates B cell growth.
    • Gives heavy chain switch from IgM to IgG , IgA and IgE.
    • Proliferation of basophils/ mast cells.
    • Can inhibit some T-cell responses.
  • IL-5
    • Activates B-cells.
    • Stimulates high rate B-cell proliferation.
    • Promotes immunoglobulin synthesis.
    • Proliferation and differentiation of eosinophils.
  • IL-6
    • Activates B-cells.
    • Stimulates high rate B-cell proliferation.
    • Promotes immunoglobulin synthesis.

Common Functions of Th₁ and TH₂ Cells

• Both TH1 and TH2 cells produce IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF).
  • These act to activate and induce proliferation of neutrophils and also macrophages.
    • Neutrophils are the major phagocytic cells in the blood and the principal cells in acute inflammatory lesions.
      • Function chiefly in the defence against extracellular bacteria.
  • Therefore, one of the major biological functions of the activation of either TH subset is cytokine-controlled reactive haematopoiesis.

T-Cell Activation

• T-cells function only after recent activation by antigen.
• CD4 binds MHC class II.
  • CD4+ T-cells therefore recognise antigen only in association with MHC class II
• CD8 binds MHC class I.
  • CD8+ T-cells recognise antigen only in association with MHC class I.
• Activation of T cells requires two distinct signals.
  • Signal 1
    • The interaction of the TcR with the antigenic peptide/MHC complex on the antigen presenting cell.
  • Signal 2
    • The interaction of CD28 on the T-cell with its ligand, CD80, on the antigen-presenting cell.
      • APC expression of CD80 only occurs after:
        • The engagement of pattern recognition or Fc receptors.
        • Activation with cytokines.
          • Interferons, IL-1β or TNFα.
      • Therefore signal 2 only occurs after the recognition of danger.

Scenarios

• No signal 1
  • T-cell is not activated as there is no antigen.
• Both signal 1 and signal 2
  • T-cell is activated into clonal expansion.
    • Produces cytokines or becomes cytotoxic.
  • This is the response to a dangerous antigen.
• Signal 1 but no signal 2
  • T-cell is triggered into apoptosis and dies.
  • This is the basis of "clonal deletion".
    • A major mechanism of tolerance.
    • Ensures that T-cells do not react with self (non-dangerous) antigens.

Response to Activation

• The response of the T cells to obtaining Signals 1 and 2 is:
  • To express the receptor for the cytokine interleukin-2 (IL-2).
  • In CD4+ T-cells only, the secretion of IL-2.
• The final trigger for clonal expansion is the engagement of IL-2R with IL-2.
  • The IL-2 can come from any activated CD4+ T-cell.
  • IL-2 produced by a CD4+ cell may also stimulate clonal expansion of that cell.

T-Helper Cell Function

• The function of T helper cells is to regulate the immune response.
  • The cytokines they secrete exert their influence on other cell populations.
    • Most of the different effector cells of the immune system are affected by one or more of the cytokines secreted by TH cells.
• TH cells secrete cytokines for only a short period after they have been activated.
• The range of cytokines that TH cells secrete after activation chiefly determines their function.
  • Different T-helper cell subpopulations secrete different sets of cytokines.
    • Th₁ and TH₂ cells.

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B Cell Development

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