Using an in vitro PBMC assay, we found that the addition of exogenous IL-21 enhances the cytotoxic potential of MAIT cells activated by 5-OP-RU. IL-21 induces STAT phosphorylation and provides co-stimulation to TCR-activated MAIT cells, selectively augmenting granzyme B and perforin expression without enhancing interferon-gamma or TNF production at 6 h.
ABSTRACT
Mucosal-associated invariant T (MAIT) cells are unconventional cytotoxic T cells restricted by MHC class 1 related molecule, MR1. They are activated through their T cell receptor (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 granzyme B 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 granzyme B and perforin on TCR or IL-12/IL-18-activated MAIT cells but has a 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.