High MDR-1 expression by MAIT cells confers resistance to cytotoxic but not immunosuppressive MDR-1 substrates

Abstract

Summary High expression of the ATP-binding cassette-multi-drug efflux protein 1 (MDR1) is a striking feature of mucosal-associated invariant T (MAIT) cells, a prominent human innate-like T cell subset. We demonstrate significantly higher MDR1 expression by CD8 + CD161 ++ Vα7.2 + MAIT cells than the phenotypically and functionally related CD8 + CD161 ++ Vα7.2-subset and show MDR1 expression to be similarly high throughout MAIT CD4+, CD8+, double-negative (DN) and double-positive (DP) cell subsets. We demonstrate the MAIT cell-predominant CD8+CD161++ subset to uniquely and efficiently efflux the cytotoxic anthracycline daunorubicin, retain function on daunorubicin exposure and demonstrate MDR1-dependent protection from daunorubicin-induced apoptosis. By contrast, CD8+CD161++Vα7.2+ MAIT cells were not protected from the anti-proliferative and cytotoxic effects of the immunosuppressive MDR1 substrates tacrolimus and mycophenoic acid, although function following MAIT cell-specific T cell receptor (TCR)-dependent and -independent stimulation was preserved on in-vitro exposure to these agents. Overall, our data further define MDR1 expression by CD161++ T and MAIT cells and demonstrate the potential for high MDR1 expression by MAIT cells to confer resistance to cytotoxic MDR1 substrates in vivo. As our understanding of the importance of MAIT cells in human immunity and immunopathology grows, this is an important observation for clinical contexts such as the treatment of malignancy, autoimmunity and post-transplant immunosuppression.