Generation of the T cell receptor repertoire in an individual

Two types of T cells are distinguished in humans and mice, according to their constituent TCR subunits -a/p or y/8. The predominant T cell type in humans and mice is the a/|3 form. The protein subunits, a, (3, y, 8, each contain a membrane-bound constant region and a variable region that recognizes the anti-gen-MHC complex. T cells originate in the thymus, where positive and negative selection ensures survival of only those T cells whose receptors can effectively recognize foreign antigens. Because thymic selection is tailored specifically to an individual's

MHC haplotypes, only a fraction of the potential diversity of the TCR repertoire is actually used.

Diversity in an individual's TCR repertoire is primarily generated as a result of two unique activities of the immune cell-specific recombination machinery: 1) rearrangement of chromosomal DNA so as to bring distantly spaced gene segments into conjunction (recombination), and 2) modification of DNA sequence at the junctions of gene segments by exonuclease nibbling and non-template-directed nucleotide addition (N-region addition). Polymorphism in variable gene segments contributes only a minor source of diversity to an individual's TCR repertoire, in contrast to the MHC. Diversity engendered by recombination is a function of the number of variable (V), diversity (D) and joining (J) gene segments in the germline TCR loci. Our current understanding of the organization of the TCR loci for human and mouse is schematized in Figure 1, and the relationship between a TCR gene, its transcript, and the polypeptide produced from the transcript is illustrated for the TCR |3 subunit in Figure 2. The a and y loci each rearrange one V gene segment to one J gene segment; the (3 locus undergoes D-J, then V-DJ recombination; and the 8 loci can rearrange V to DJ or V to DDJ. Several of the Va genes in human and mouse can rearrange to either a DJ segment of the 8 locus or a J segment of the a locus. Once rearrangement of the TCR loci has occurred, permanently altering the chromosomal DNA of the T cell, a TCR of either the a/|3 or y/8 subunits is produced from the mRNAs generated by transcription and splicing of the rearranged gene segments. Generally, only one a/(3 or y/8 combination is allowed per T cell. Thus, the immune cell-specific recombination machinery ensures TCR uniqueness at the level of individual T cells and their descend-ents, and diversity in the TCR repertoire as a whole.

TCR loci differ from subunit to subunit and species to species in the number of germline gene segments capable of undergoing rearrangement. For

14 Variable gene segments in 4 subfamilies

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