The vast majority of cell-based anticancer therapies aims at harnessing peculiar effector functions of polymorphic MHC-restricted conventional T cells. Recent data suggested that CD4+ TH9 cells are endowed with potent antitumor functions upon adoptive T cell transfer. Interestingly, innate T cells, which react to monomorphic MHC class I-like molecules, also share core "immune modules" that include transcriptional network and effector functions. However, existence of innate T cells with a TH9 profile has never been reported.
Here, we evidence that human MAIT cells from healthy donors can be expanded and differentiated into MAIT9 cells based on their transcriptional signature and cytokine profile. Of note, the use of IL-1β boosted MAIT cell differentiation towards the TH9 profile. Using single cell RNA-sequencing, we revealed the transcriptional circuitry that accompanies MAIT9 differentiation as compared to CD4+ TH9 cells. Importantly, MAIT9 cells exerted direct MR1-dependent cytotoxic properties against two cell lines, a killing activity that was superior to MAIT0 cells. Thus, our data support the interest of harnessing innate T cells, including MAIT cells for innovative T cell-based anti-tumor therapy.