Ordered and Coordinated Rearrangement of the TCR α Locus: Role of Secondary Rearrangement in Thymic Selection

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Abstract
The Ag receptor of the T lymphocyte is composed of an αβ heterodimer. Both α- and β-chains are products of the somatic rearrangement of V(D)J segments encoded on the respective loci. During T cell development, β-chain rearrangement precedes α-chain rearrangement. The mechanism of allelic exclusion ensures the expression of a single β-chain in each T cell, whereas a large number of T cells express two functional α-chains. Here we demonstrate evidence that TCR α rearrangement is initiated by rearranging a 3′ Vα segment and a 5′ Jα segment on both chromosomes. Rearrangement then proceeds by using upstream Vα and downstream Jα segments until it is terminated by successful positive selection. This ordered and coordinated rearrangement allows a single thymocyte to sequentially express multiple TCRs with different specificities to optimize the efficiency of positive selection. Thus, the lack of allelic exclusion and TCR α secondary rearrangement play a key role in the formation of a functional T cell repertoire.