Department of Immunology, Duke University Medical Center, Durham, NC.
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC.
J Exp Med. 2022 Feb 7;219(2). doi: 10.1084/jem.20211581. Epub 2021 Dec 15.
The Tcra repertoire is generated by multiple rounds of Vα-Jα rearrangement. However, Tcrd recombination precedes Tcra recombination within the complex Tcra-Tcrd locus. Here, by ablating Tcrd recombination, we report that Tcrd rearrangement broadens primary Vα use to diversify the Tcra repertoire in mice. We reveal that use of Trav15-dv6 family V gene segments in Tcrd recombination imparts diversity in the Tcra repertoire by instigating use of central and distal Vα segments. Moreover, disruption of the regions containing these genes and their cis-regulatory elements identifies the Trav15-dv6 family as being responsible for driving central and distal Vα recombinations beyond their roles as substrates for Tcrd recombination. Our study demonstrates an indispensable role for Tcrd recombination in general, and the Trav15-dv6 family in particular, in the generation of a combinatorially diverse Tcra repertoire.
Tcra 受体库是通过多轮 Vα-Jα 重排产生的。然而，在复杂的 Tcra-Tcrd 基因座内，Tcrd 重组先于 Tcra 重组发生。在这里，通过消除 Tcrd 重组，我们报告 Tcrd 重排拓宽了主要的 Vα 使用范围，从而使小鼠的 Tcra 受体库多样化。我们揭示了 Trav15-dv6 家族 V 基因片段在 Tcrd 重组中的使用通过引发对中央和远端 Vα 片段的使用，赋予了 Tcra 受体库多样性。此外，破坏包含这些基因及其顺式调控元件的区域将 Trav15-dv6 家族确定为负责驱动中央和远端 Vα 重组的原因，超出了它们作为 Tcrd 重组底物的作用。我们的研究表明，Tcrd 重组在一般情况下，特别是 Trav15-dv6 家族在产生组合多样化的 Tcra 受体库方面具有不可或缺的作用。
