Unconventional T cells, namely MAIT, NKT, and γδT cells, recognise non-peptide antigens presented by non-classical MHC-like molecules, and can rapidly mount robust cytokine responses after activation, leading to their implication in modulating the host immune response to disease. In particular, MAIT cells recognise riboflavin biosynthesis metabolites, such as 5-OP-RU, presented by MR1, and utilise a semi-invariant TCR comprising a Trav1-Traj33+ TCRα chain that pairs with a limited range of TCRβ chains. Despite their relative abundance, MAIT cell frequencies vary widely between individuals, ranging from 0.1-10% of total blood T cells in humans, the cause of which is understudied. Recent evidence has suggested that MAIT and other unconventional T cells may co-exist in the body within a shared developmental or homeostatic niche and are regulated by similar genetic and/or environmental factors.
We confirm earlier findings that CD1d-deficient mice, which lack NKT cells, have increased MAIT cells, and show that this is due to the loss of NKT cells rather than CD1d itself. Likewise, MAIT cells are also markedly increased in TCRδ-deficient mice, which lack γδT cells, and further expand in CD1d/TCRδ-doubly deficient mice. Expanded MAIT cells phenotypically and functionally resemble their WT counterparts. Accordingly, we hypothesise that MAIT cells may compete with NKT and γδT cells for similar factors and subsequently expand in their absence. As increased MAIT cells were also observed in the thymus, we sought to investigate Trav1-Traj33 rearrangements and found that they were increased within developing thymocytes from TCRδ- and CD1d/TCRδ-doubly deficient mice. Consequently, we hypothesise that modification of the TCRδ locus to create TCRδ-deficient mice may have affected TCRα rearrangements during T cell development, in particular resulting in greater usage of distal Trav gene segments such as Trav1.
Thus, in addition to providing insight into factors that affect MAIT cell frequencies, our work also sheds light on previously unappreciated alterations in TCRα chain rearrangements in TCRδ-deficient mice, and cautions the use of CD1d- and TCRδ-deficient mice for studying the role of NKT and γδT cells in disease, respectively.