Tcrd Rearrangement Redirects a Processive Tcra Recombination Program to Expand the Tcra Repertoire

Adaptive immunity depends on diverse T cell receptor repertoires generated by variable, diversity, and joining (V[D]J) recombination. Here, we define the principles by which combinatorial diversity is generated in the murine Tcra repertoire. Tcra and Tcrd gene segments share the Tcra-Tcrd locus, with interspersed V α and V δ segments undergoing V δ -D δ -J δ rearrangement in CD4 − CD8 − thymocytes and then multiple rounds of V α -J α rearrangement in CD4 + CD8 + thymocytes. We document stepwise, highly coordinated proximal-to-distal progressions of V α and J α use on individual Tcra alleles, limiting combinatorial diversity. This behavior is supported by an extended chromatin conformation in CD4 + CD8 + thymocytes, with only nearby V α and J α segments contacting each other. Tcrd rearrangements can use distal V δ segments due to a contracted Tcra - Tcrd conformation in CD4 − CD8 − thymocytes. These rearrangements expand the Tcra repertoire by truncating the V α array to permit otherwise disfavored V α - J α combinations. Therefore, recombination events at two developmental stages with distinct chromatin conformations synergize to promote Tcra repertoire diversity.