Lecture 9 - T cell development and tolerance

• Types of T Cell Receptor

  • Alpha-beta receptor
  • Gamma-delta receptor
• Alpha-beta receptor


  • Composed of two different chains, alpha and beta
• Gamma-delta receptor


  • Contains a different set of chains, one gamma and one delta
• TCR


  • Found only on the cell membrane
  • Consists of two polypeptide chains
  • Each T cell may have as many as 30,000 receptor molecules on its membrane surface
  • The TCR molecule is embedded in the membrane of the cell, and a portion of the molecule extends away from the cell surface into the surrounding area
  • The chains each contain two folded domains, one constant and one variable, similar to the structure of antibody molecules
  • The variable domains of the chains form an antigen-binding site, with the TCR having only one antigen-binding site, unlike the basic antibody molecule, which has two
• Formation of the TCR

  1. TCRs are formed during the development of T cells in the thymus

  2. The T cell receptor genes undergo rearrangement to achieve diversity, similar to the process of antibody diversity generation in B cells

  3. TCR must make contact with both the peptide and the MHC molecule, and it aligns diagonally over the peptide-MHC complex

  4. The TCR has flexibility and can undergo an induced fit to enable better contact with different peptides
• 23-12 Rule


  • The requirement for recombination signal sequences (RSS) of different spacer length (either 12 or 23 base pairs) to efficiently recombine during VDJ recombination
  • This rule ensures that gene segments flanked by 12RSS can only recombine with gene segments flanked by 23RSS, and vice versa
• Thymus


  • Bi-lobed structure with each lobe being identical
  • Sits above the heart and undergoes age-driven atrophy (shrinkage)
• Developmental pathway for T cells

  1. Transformation of pluripotent haematopoietic stem cells (HSCs) to common lymphoid progenitors (CLPs) in the bone marrow

  2. CLPs with NK, B and T cell potential enter the thymus via blood vessels at the cortical/medullary junction

  3. Signals from thymic stromal cells commit CLPs to the T cell lineage

  4. Committed cells move to the cortex where they undergo positive selection

  5. Positively selected cells move to the medulla where they undergo negative selection

  6. Only cells that pass positive and negative selection are allowed to leave the thymus and recirculate in the blood
• Positive Selection


  • Ensures that developing T cells are capable of recognizing and binding to MHC complexes, which is essential for their ability to fight pathogens and foreign cells
  • Determines whether a T cell will become a CD8+ or a CD4+ T cell, based on the strength of the TCR binding to MHC class I or class II molecules
• Negative Selection


  • Ensures that T cells do not recognize and attack our own cells, preventing autoimmunity
  • Involves the removal of T cells that carry receptors for peripheral tissue-restricted peptides presented by MHC molecules from the T cell repertoire
• Process of Positive Selection

  1. Occurs in the thymic cortex, where cortical thymic epithelial cells (cTECs) express both MHC class I and II molecules

  2. Developing T cells with TCRs capable of binding to MHC complexes receive survival signals and are positively selected, while those incapable of binding undergo apoptosis

  3. Strength of interaction of the TCR with MHC defines the fate of the T cell, determining whether it becomes a CD4+ or CD8+ T cell
• Role of mTECs and cTECs

  • Medullary thymic epithelial cells (mTECs) in the thymic medulla express both MHC class I and II molecules with self-peptides, contributing to negative selection
  • T cells that survive positive selection move to the medulla, where mTECs and thymic dendritic cells participate in negative selection
  • The transcription factor Autoimmune Regulator (AIRE) induces the transcription of tissue-restricted antigens (TRAs) in mTECs, exposing developing T cells to a wide range of self-peptides to prevent autoimmunity