IMMUNOLOGY - Roit I. - Mir 2000

Chapter 8. Sources of Diversity in Antigen-Recognizing Structures

GENES OF THE ANTIGEN-RECOGNIZING T-CELL RECEPTOR

The TCR structures responsible for binding antigen and MHC molecules are encoded by four distinct groups of genes. The genes for the α- and β-chains are expressed by the majority of peripheral T Cells, whereas those for the γ- and δ-chains are expressed by a subpopulation of thymocytes and a minor population of peripheral T cells. Two pairs of chains (α/β or γ/δ), associated with the γ, δ, ε, and ζ chains of the CD3 polypeptide complex, form the complete TCR (see Chapter 7).

The overall chromosomal Organization of TCR genes bears a striking resemblance to that of immunoglobulin heavy chain genes. Interestingly, the TCR δ-genes, along with their entire sets of D-, J-, and C-segments, are located within the α-Gene cluster (Fig. 8.25).

Class="center">

Fig. 8.25. The recombination mechanism of TCR genes is similar to that of immunoglobulin heavy chain genes. The diagram illustrates the arrangement of genes within the mouse T-Cell receptor α-, δ-, β-, and γ-chain loci. The δ-chain genes are embedded within the α-chain locus. The β-chain locus contains two clusters of tandemly duplicated J-segments. The final segments of each Jβ cluster and the Vγ3 segment are pseudogenes.

TCR gene diversity is generated by V-D-J recombination with minor variations specific to each locus

At first glance, the gene segments encoding the α-chain appear straightforwardly arranged. The only complexity arises from the fact that the V, D, and J loci of the δ-chain are interspersed between the V and J loci of the α-chain. Much like the V regions of immunoglobulin κ-chains, the V regions of TCR α-chains are encoded by a gene formed through the recombination of Vα and Jα segments. The degree of α-chain Variability is substantially amplified by an unusually large number of Jα segments.

The β locus comprises two sets of D, J, and C segments. Most Vβ segments are clustered together, but one (Vβ14) is located at the 3'-end of the locus. The tandem duplications of the Dβ, Jβ, and Cβ gene segments apparently arose quite early in mammalian evolution, as they are present in both mice and humans. Extensive diversity in the β-chain is generated during recombination, since the various V-D-J rearrangements are further augmented by V-J and V-D-DJ combination variants. The utilization of all three reading frames of the D segments provides an additional layer of diversity.

The arrangement of gene segments within the γ-chain locus differs markedly between mice and humans. The mouse locus bears a striking resemblance to the immunoglobulin light chain locus, containing four Cγ genes (including one pseudogene), each of which can associate with a single J segment and join one to four Vγ segments. There are no D segments in the γ-chain locus. In humans, there are eight Vγ segments, followed upstream (5') by three Jγ segments, a Cγ1 gene, two additional Jγ segments, and a Cγ2 gene. A significant contribution to γ-chain diversity is made by junctional inaccuracies during the joining of V and J segments, as well as the insertion of additional NUCLEOTIDES at these junction sites.

The δ-chain locus (discovered during The Study of the α locus) has a relatively simple organization, containing only five Vδ, two Dδ, and six Jδ segments; however, the estimated number of potential δ-chain variants arising from junctional inaccuracy, nucleotide insertions, and The Use of all three reading frames of D segments reaches 10¹⁴.

TCR genes apparently share a recombination mechanism similar to that of B-cell Ig genes, given the conserved nature of their flanking recombination signal sequences (a heptamer, a 12- or 23-nucleotide spacer, and a nonamer). Similar or identical recombination Enzymes operate in both B AND T cells; TCR Dβ and Jβ gene segments experimentally transfected into B cells are capable of undergoing proper recombination. A notable expansion of 'N-region' variability also contributes substantially to TCR diversity.

Somatic mutagenesis, which serves as such a vital source of immunoglobulin diversity, leaves no footprint in TCR genes. This is likely because T cells must recognize MHC products while maintaining tolerance to the Organism's own self-Antigens.