Unconventional T cells, namely MAIT, NKT, and γδT cells, recognise non-peptide antigens using T cell receptors (TCRs) of limited diversity, and exhibit rapid, ‘innate-like’ functions. In particular, MAIT cells recognise microbial riboflavin metabolites via their invariant Trav1-Traj33+ TCRα chain and potently secrete IL-17 and IFN-γ upon activation. Notably, MAIT cells comprise 0.1-10% of circulating T cells in humans, the cause of this wide variance in frequency being poorly understood. Recent evidence has suggested that MAIT, NKT, and γδT cells may be regulated by similar environmental or genetic factors and may reside within a shared niche.
We showed that NKT cell-deficient mice have increased MAIT cells and demonstrated that this increase was due to the loss of NKT cells rather than their restricting element, CD1d. MAIT cells were also markedly increased in γδT cell-deficient mice and expand further in NKT/γδT cell double-deficient mice. Expanded MAIT cells phenotypically and functionally resembled their wildtype (WT) counterparts. As MAIT cells were increased in the thymus, we analyzed Trav1-Traj33 transcripts within developing thymocytes and showed that overall Trav1-Traj33 transcript levels were increased 2-fold within γδT- and NKT/γδT-deficient thymocytes relative to WT controls. As γδT-deficient mice harbor a modified TCRδ locus, our findings imply that TCRα rearrangement may be altered in these mice, potentially manifesting in greater rearrangement of distal Trav gene segments like Trav1 and increased intrathymic generation of MAIT cells. However, increases in peripheral MAIT cells exceeded increases in the thymus, indicating that MAIT cells may compete with peripheral NKT and γδT cells for similar homeostatic factors and expand in their absence. Accordingly, we show that adoptively transferred MAIT cells underwent more proliferation within NKT/γδT-deficient hosts relative to WT controls.
Together, our findings highlight a shared niche in which MAIT, NKT, and γδT cells co-exist and compete for common homeostatic factors. Importantly, these findings provide insights into factors regulating MAIT cell levels and cautions the interpretation of studies on NKT and γδT cells using NKT- or γδT-deficient mice, respectively, due to previously unappreciated increases in MAIT cell levels and potential alterations in TCRα chain rearrangement in γδT-deficient mice.