IL-21 selectively augments cytotoxic potential of antigen-activated MAIT cells

Mucosal-associated invariant T (MAIT) cells are unconventional cytotoxic T cells restricted by MHC class 1 related molecule, MR1. They are activated through their TCR by derivatives from microbial riboflavin synthesis or independently of TCR signalling via IL-12 and IL-18. Upon activation, MAIT cells upregulate cytotoxic molecules GrzB and perforin and lyse bacterially-infected cells. While cytokines act as co-stimulatory molecules that enhance MAIT cell activation, their specific role in regulating MAIT cell cytotoxicity remains unresolved. We show that the cytokine IL-21 enhances expression of GrzB and perforin on TCR or IL-12/IL-18-activated MAIT cells but has limited effect on MAIT cell cytokine production. Using a flow cytometry-based cytotoxic assay, we show priming MAIT cells with IL-21 enhances their ability to kill 5-OP-RU-treated B cell lines. We demonstrate a previously unexplored co-stimulatory role for IL-21 that selectively augments the cytotoxic potential of MAIT cells.