biostudies-literatureDauphars DJNIAID NIH HHSNational Institutes of HealthNIH HHSNIGMS NIH HHSe20211581https://www.ebi.ac.uk/biostudies/studies/S-EPMC8679779biostudies-literatureUnknown219(2)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.The Journal of experimental medicineTrav15-dv6 family Tcrd rearrangements diversify the Tcra repertoire.PMC8679779P01 AI102853R01 GM41052T32 AI052077R01 GM041052R35 GM136284Dauphars DJMihai AKrangel MSWang LZhuang YfalseTrav15-dv6 family Tcrd rearrangements diversify the Tcra repertoire.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.2022-01-01T00:00:00Z2022 Feb2025-04-05T14:59:03.893Z2025-04-05T14:59:03.893ZS-EPMC86797793491010710.1084/jem.20211581