Expansion of MAIT cells in the combined absence of NKT and γδ-T cells

Abstract

Mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and γδT cells are collectively referred to as 'unconventional T cells' due to their recognition of non-peptide antigens and restriction to non-classical MHC-I-like molecules. Though the frequencies of MAIT, NKT and γδT cells and distribution of their functional subsets vary widely between organs and individuals, the factors controlling these differences are poorly understood. Here, we show that MAIT cells are increased in mice deficient in either NKT or γδT cells and even more-so in mice deficient in both NKT and γδT cells. In addition, characterisation of the TCRα repertoire within γδT cell-deficient thymocytes revealed an altered Trav gene segment usage relative to that of WT thymocytes, highlighting a retention of the Tcra-Tcrd locus from 129 strain embryonic stem cells used to generate Tcrd-/- mice. Accordingly, this resulted in a moderate increase in distal Trav segment usage such as Trav1, potentially contributing to increased generation of Trav1-Traj33+ MAIT cells in the Tcrd-/- thymus. However, peripheral MAIT cells also underwent increased homeostatic proliferation in the absence of NKT and γδT cells and adoptively transferred MAIT cell subsets exhibited tissue-specific homing patterns. Collectively, our data reveals a shared niche for MAIT, NKT, and γδT cells, suggesting a competition for common factors that could be exploited for treating disease. Importantly, these data highlight that careful assessment of studies using NKT or γδT cell-deficient mouse models is required when investigating the role of unconventional T cells in disease.