Immunogenetics Lecture 3: TcR

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

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

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

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.

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

Lymphocytic development (maturation)

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

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

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

Organization of TcR genes

Diversity in the TCR gene locus

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

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.

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

Summary: Ig vs TCR

Summary: mechanisms that generate diversity in lymphocyte receptors