Programmed cell death (PCD) pathways are critical to shaping the immune response during infection, both regulating and being influenced by immune inflammation. PCD encompasses a broad range of pathways including the immunologically silent apoptotic program, and the lytic inflammatory PCD programs of necroptosis and pyroptosis. The mechanisms regulating apoptosis in conventional T cell subsets are relatively well studied, and emerging evidence demonstrates that conventional T cell subsets also utilise inflammatory cell death machinery in some contexts. However, we know little about the regulation of PCD pathways in unconventional T cell subsets such as mucosal associated invariant T (MAIT) cells. Given the long lived nature of MAIT cells in vivo and differences in their proliferative capacity, effector function and response kinetics compared with unconventional T cell subsets, it is important to understand the regulation of PCD in MAIT cells.
We have recently shown that MAIT cells express the core necroptotic machinery in murine models1. Here we show that human MAIT similarly express this same machinery including both receptor-interacting protein kinases (RIPK1 and RIPK3), and the terminal necroptotic effector mixed lineage kinase-domain like pseudo kinase (MLKL). Commensurate with their expression of MLKL, we show that MAIT cells are susceptible to death following treatment with the canonical necroptotic cocktail of TNF, smac mimetic and the caspase inhibitor IDUN (TSI). This death correlates an early loss of MLKL, and is rescued by inhibition of either MLKL or RIPK3; thus demonstrating a functional necroptotic PCD pathway in MAIT cells activated in inflammatory contexts.
This work opens exciting avenues of future investigation into the role of lytic cell death in MAIT cells, and T cell more broadly. Understanding how these inflammatory pathways may be harnessed to mediate the control of infection, or potentiate chronic inflammation, possibly opening new targets for therapeutic intervention.