Somatic hypermutation of T cell receptor gamma, delta, and beta chains in nurse sharks

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Abstract Many γδ T cells typically bind antigen in a manner similar to that of immunoglobulins, recognizing and directly binding small molecules and intact proteins without presentation by classical MHC:Ag complexes. In this way, γδ T cells combine an innate-like immune response with an adaptive recognition strategy, providing both an immediate response to pathogen invasion and an ongoing, adaptive response to inflammation. However, γδ T cells often recombine tissue-specific, restricted sets of genes that have limited junctional diversity. Thus, somatic hypermutation (SHM) presents a useful solution for diversifying these antibody-like T cell receptors (TCR) by fine-tuning ligand recognition or permitting changes within the loci that allow receptors to evolve more rapidly to changing ligand environments. In fact, recent studies in sandbar shark have confirmed definitively that the γ chain locus of γδ T cells employs SHM as a mechanism to generate more diverse γδ TCR, and follow-up studies in dromedary camel indicated that loci of both γ and δ chains use SHM to diversify γδ TCR. In nurse sharks, we found evidence that SHM acts in the thymus, altering the α chain locus of αβ T cells to broaden the primary αβ T cell repertoire. Further, early results suggest that SHM modifies both γ and δ chain loci (but not β chain locus of αβ T cells) and this alteration may occur in the thymus, indicating that this receptor fine-tuning may precede ligand recognition.