1. Immunogenetics
Lecture 3: TcR

2. TCR Definition of terms Structure of TCR Development of TCR
The similarities and differences between TcR and antibodies
The structure and organisation of the TcR genes
Somatic recombination in TcR genes
Generation of diversity in TcR
Why TcR do not undergo somatic mutation
TCR and MHC interactions

3. Definition of TCR
The T-cell receptor (TCR) is a protein that binds to peptide antigens presented by MHC proteins.

4. TCR structure Two polypeptide chains, a and b
Variable & constant domains
Single Ag binding site
Lower affinity than Ab
Ag must be bound to MHC
CD4 (TH) or CD8 (TC) also binds MHC
Signal transduction by CD3 and ζ

5. Structure of TCR
The TCR protein has 2 subunits and one antigen binding site.
The alpha subunit has V and J segments (similar to Ig light chains)
The beta subunit has V, D and J regions, like the Ig heavy chain.
Both segments undergo DNA splicing rearrangements like the Ig genes. The joining is not precise and short additions or deletions of bases can occur, as in the Ig genes.
However, affinity maturation and somatic hypermutation do not occur.
The TCR protein is membrane bound and is only found on T cells.

7. Lymphocytic development (maturation)
Stem cells in bone marrow
Precursor cells
Proliferate
Rearrange receptor genes
Test for functional receptor
Immature cells
Positive selection
Negative selection
Mature cells

8. Lymphocytic development (maturation)

9. T cell development Stem cells in bone marrow pro-T cell thymus
double negative: no CD4 or CD8
Interact w/thymus stromal cells
IL-7 stimulates proliferation
Recombination of b-chain gene
b associates with pre-Ta
pre-T cell with pre-TCR
pre-TCR signals:
Alleleic exclusion for b gene
Expression of CD4 and CD8
Proliferation
Recombination of a gene
no pre-TCR apoptosis

10. Changes in immunoglobulin and TCR genes that occur during B-cell and T-cell development and differentiation

11. TCR Genes and Diversity
The V domain of the  chain of the TCR is encoded by V, D, and J gene segments.
V and J gene segments encode the V domain of the  chain of the TCR

12. Organization of TcR genes

13. Diversity in the TCR gene locus

14. T cell antigen receptor diversity
Unlike MHC molecules TcR are highly variable in the individual
Diversity focused on small changes in the charge & shape presented at the end of the T cell receptor.
TcR diversity to the peptide antigens that bind to MHC molecules
Mechanisms of diversity closely related to T cell development
Random aspects of TcR construction ensures maximum diversity
Mechanisms of diversity generation similar to immunoglobulin genes

15. Generation of diversity in TcR
Diversity generated by
Somatic recombination,
Reassortment of gene products,
transcription of D regions in three reading frames, and
random N nucleotide addition ensure practically unlimited antigen-binding TCRs.

16. Generation of diversity in the TcR
COMBINATORIAL DIVERSITY
Multiple germline segments, In the human TcR
Variable (V) segments: ~70, 52
Diversity (D) segments: 0, 2
Joining (J) segments: 61, 13
The need to pair  and  chains to form a binding site doubles the potential for diversity
JUNCTIONAL DIVERSITY: Addition of non-template encoded (N) and palindromic (P) nucleotides at imprecise joints made between V-D-J elements
Somatic mutation is not used to generate diversity in TCR

17. Summary: Ig vs TCR

18. Summary: mechanisms that generate diversity in lymphocyte receptors