NKT and MAIT invariant TCRα sequences can be produced efficiently by VJ gene recombination.

Semi-invariant T cell receptors (TCRs) found on natural killer T (NKT) and mucosal-associated invariant T (MAIT) cells are characterized by the use of invariant variable (V) and joining (J) gene combinations in the TCR α-chain, as well as ubiquitous canonical TCRα amino acid sequences that are dominant in many individuals and similar across species. That they are so prevalent indicates that they occupy an important niche within the immune system. However, these TCRs are produced by a largely random gene recombination process, which seems a risky approach for the immune system to acquire these innate-like cells. We surveyed studies reporting NKT and MAIT TCRα sequences for six and four different species, respectively. Although the germline nature of the canonical human and mouse NKT and mouse MAIT TCRα sequences and an overlap of nucleotides between the mouse MAIT-related Vα and Jα genes have been noted in previous studies, in this study we demonstrate that, for all reported species, the canonical TCRα amino acid sequences can be encoded by at least one germline-derived nucleotide sequence. Moreover, these nucleotide sequences can utilize an overlap between the Vα and Jα genes in their production, which enables them to be produced by a large variety of recombination mechanisms. We investigated the role of these TCRα features in the production of the canonical NKT and MAIT TCRα sequences. In computer simulations of a random recombination process involving the invariant NKT and MAIT TCRα gene combinations for each species, the canonical NKT and MAIT TCRα sequences were the first or second most generated of all sequences with the CDR3α length restrictions associated with NKT and MAIT cells. These results suggest that the immune machinery enables the canonical NKT and MAIT TCRα sequences to be produced with great efficiency through the process of convergent recombination, ensuring their prevalence across individuals and species.