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

Publication date: 6 June 2017
Source:Cell Reports, Volume 19, Issue 10
Author(s): Zachary M. Carico, Kingshuk Roy Choudhury, Baojun Zhang, Yuan Zhuang, Michael S. Krangel
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 Vα and Vδ segments undergoing Vδ-Dδ-Jδ rearrangement in CD4⁻CD8⁻ thymocytes and then multiple rounds of Vα-Jα rearrangement in CD4⁺CD8⁺ thymocytes. We document stepwise, highly coordinated proximal-to-distal progressions of Vα and Jα use on individual Tcra alleles, limiting combinatorial diversity. This behavior is supported by an extended chromatin conformation in CD4⁺CD8⁺ thymocytes, with only nearby Vα and Jα segments contacting each other. Tcrd rearrangements can use distal Vδ segments due to a contracted Tcra-Tcrd conformation in CD4⁻CD8⁻ thymocytes. These rearrangements expand the Tcra repertoire by truncating the Vα array to permit otherwise disfavored Vα-Jα combinations. Therefore, recombination events at two developmental stages with distinct chromatin conformations synergize to promote Tcra repertoire diversity.

Graphical abstract

Teaser

A diverse Tcra repertoire is essential for robust adaptive immunity. Carico et al. demonstrate that the Tcra repertoire is intrinsically limited by a processive recombination program. Tcrd recombination overcomes this constraint to broaden Vα-Jα combinatorial diversity, and it is important for the development of MAIT cells, an innate-like αβ T cell subset.


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