Medicine & USMLE

T Cells - Differentation

B Cells and T Cells
  1. MHC I
  2. MHC II
  3. B Cells - Overview
  4. B Cells - Activation
  5. Plasma B Cells
  6. Memory B Cells
  7. T Cells - Overview
  8. T Cells - Activation
  9. T Cells - Differentation
  10. Cytotoxic (Killer) T Cells
  11. Helper T Cells - Overview
  12. Th1 Cells
  13. Th2 Cells
  14. Th17 Cells
  15. Regulatory T Cells (Tregs)


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