T cell receptors

T cell receptors

Bone marrow dervied lymphocytes, mature in thymus, express the CD3-TCR complex.
1. 2 Forms: αβ found on CD4+ve T helper cells and CD8 cytotoxic cells/ γδ TCR 1-10% of T cells
  1. T cell receptors are clonally distributed, generated by somatic recombination
Structure of αβ TCR- 3 hypervariable regions directly involved in Ag binding.
1. Both forms of the TCR receptor are associated wirh rh polypeptide of the CD3 complex.CD3= 4 Invariant polypeptides necessary for TCR surface expression which act in signal transduction following specific Ag recognition by the TCR.
Ag recognition
1. T cells recognise Ags presented by other cells in the body. Do not bind free or soluble Ags like Abs
2. For αβ TCRs-Ags are recognised as short peptides 9-13AA, along with the MHC molecule. Only recognises when bound to MHC
3. γδ Ag recognition less understood
4. CD4+ve T helper-Class II/ CD8+ cytotoxic-class I. Specificity at level of the T cell not MHC
Somatic recombination
1. =T cell diversity. In the thymus during T cell differentiation
2. Mechanistically rearrangrment of the TCR genes resembles that of the Ig gene but with some subtle differences.
3. Alpha rearrangement
  1. ~75 variable, 61 joining, 1 constant- rearrangement to form VJ-txn-trans=polypeptide
  2. ~5000
4. Beta rearrangement
  1. 60 variable, diversity, joining and constant-DJ rearrangement followed by VDJ second rearrangement=polypeptide
  2. ~1,500
5. γδ TCR genes- δ is located within the α gene loci
  1. 60 y & ~150 δ
6. Junctional diversity
  1. Nibbling of several bases at 3' end of V gene and 5' end of D/J gene=imprecise joining. Up to 3 'palindromic' nucleotides can be added: Insertion of up to 10 random bases, not coded by TCR genes=N-region addition. Dδ gene segments can be read in all three reading frames
7. T cell diversity αβ- combinatorial diversity gives (5000 x 1500)= 10^7 + junctional diversity= 10^10
  1. T cell diversity γδ- combinational diversity (60 x 150)= 9000 + junctional diversity=much higher
Gene rearrangement in the thymus
1. recombination signal sequences regulate rearrangement of gene segments. Heptamer-nonomer sequences seperated by 12/ 23 bases (see sheet).
  1. Mediated by RAG1 & 2 genes
    1. more diversity is concentrated at the third hypervariable region because -terminal deoxytransferase can randomly add up to 10 nts at all joints -D region genes can be read in all reading frames (δ gene)
2. TCR b, γ & δ gene rearrangements start together on both chs. Producxtive rearrangements supress further rearrangement of homologous chs- TCR a genes rearranged last
  1. T cell lineage determination
Interaction of TCR with MHC + peptide
1. V regions including CDRs 1 + 2 interact with MHC. (D-)J regions comprising CDRs3 interact with MHC bound peptide

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