T Cells - Differentation

Summary

T-Cell Differentiation is the process by which immature T-cell precursors turn into mature Cytotoxic and Helper T-cells. This happens in several steps which take place in different locations throughout the body.

All immature T-cell precursors originate in the bone marrow from lymphoid progenitor cells. These cells are double-negative, meaning that they do not express CD8 or CD4 on their surface.

Afterwards, these immature T-cell precursors migrate to the thymic cortex to mature. Once in the thymic cortex, immature T-cells express both the CD4 and CD8 markers, making them double-positive T-cells. In addition, these immature T-cells rearrange their T-cell receptor genes to create functional receptors capable of binding many types of antigens. To ensure that these T-cell receptors are capable of binding to MHC (doing their job), these T-cells undergo positive selection, meaning that they must be able to bind to MHC in order to survive.

Subsequently, these double-positive T-cells migrate into the thymic medulla. In the thymic medulla, T-cells undergo negative selection -- meaning that T-cells that bind too tightly to self-MHCs are eliminated, helping to prevent autoimmunity. In the thymic medulla, T-cells also become single-positive, expressing just one surface marker: CD4 or CD8. These cells are now mature killer or helper T-cells.

Finally, these mature killer and helper T-cells leave the thymus to migrate to lymphoid tissue, where they wait for the right antigen to come along to activate their effector functions. 

Key Points

• T Cell Differentiation
  • Process by which immature T-cell precursors differentiate into mature CD4 or CD8 subsets 
  • Begins in bone marrow
    • Do not express CD4 or CD8 (double-negative)
    • Do not express TCR
    • Immature T cells migrate from bone marrow to thymic cortex to develop
  • Migrate to thymic cortex 
    • Express both CD4 AND CD8 (double-positive)
    • TCR gene rearrangement takes place
      • Beta gene rearranges before alpha gene
      • Rearrangement enables recognition of a variety of antigens
      • Also produces failed TCRs, which are eliminated by positive selection
    • Undergoes positive selection
      • T-cells must bind self-MHC to survive
        • self-MHC expressed by thymic cortical epithelial cells
  • Move to thymic medulla 
    • Express CD4 OR CD8 (single-positive)
    • Undergoes negative selection
      • T cells with overly high affinity for self-antigens/MHC undergo apoptosis or become regulatory T cells
        • Tissue-restricted self-antigens expressed on thymic medullary epithelial or dendritic cells due to action of autoimmune regulator (AIRE); deficiency can lead to autoimmune polyendocrine syndrome-1
  • Migrate to lymphoid tissues
    • Mature single-positive (CD4+ or CD8+) T cells
    • migrate to spleen, lymph nodes, and tonsils to reside