TCR diversity

T lymphocytes, like their B cell counterparts, must handle a huge number of foreign antigens. Elegant mechanisms have evolved to generate a vast diversity while refraining from overburdening the genome with too many different sequences. An estimate of the total potential of TCR diversity before thymic selection of T cells is summarized in Table 1. For TCRa and TCRf3 chain genes, diversity is created in two key ways: through the germ line and through junctional and N-region diversity. Germline diversity is the summation of all the possible combinatorial joinings between the V, D and J gene segments of each gene locus, as well as the association between the products of the TCRa and TCR(B genes. Junction diversity is the result of an imprecise joining between the V, D and J gene segments, leading to codon changes at the junctions. N-region diversity is generated by the addition of nucleotides (that are not coded by rearranging germline segments) to the V-D-J junctions during the rearrangement process. Assuming the insertion of three different codons at each junction, this process yields a potential 104 (20 X 20 X 20) different combinations of N-region diversity.

Both these processes substantially increase the repertoire of TCR sequences, but also produce a large number of nonfunctional genes by shifting the reading frame. Somatic hypermutation, which generates point mutations throughout the variable regions of BCR molecules, does not appear to occur in either the TCRa or TCR(3 genes, although there has been a single report that hypermutation occurs in TCR. One hypothesis is that, while somatic hypermutation can occur in T cells, it is a rare event because of the lack of selection pressure in vivo for the expansion of hypermutated cells. Such cells might exhibit a lower

Table 1 Estimate of human TCR repertoire

Gene segment

a chain

ß chain

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