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 and V segments undergoing V-D-J rearrangement in CD4CD8 thymocytes and then multiple rounds of V-J rearrangement in CD4CD8 thymocytes. We document stepwise, highly coordinated proximal-to-distal progressions of V and J use on individual Tcra alleles, limiting combinatorial diversity. This behavior is supported by an extended chromatin conformation in CD4CD8 thymocytes, with only nearby V and J segments contacting each other. Tcrd rearrangements can use distal V segments due to a contracted Tcra-Tcrd conformation in CD4CD8 thymocytes. These rearrangements expand the Tcra repertoire by truncating the V array to permit otherwise disfavored V-J combinations. Therefore, recombination events at two developmental stages with distinct chromatin conformations synergize to promote Tcra repertoire diversity.