Altered MAIT cell activation characteristics with impaired IL-10 and IL-17A response programs in active Crohn's...

Mucosa-associated invariant T (MAIT) cells are innate-like MR1-restricted T cells broadly distributed in human tissues. MAIT cells adapt their antigen-specific response patterns depending on cytokine cues such as IL-12 or IL-18 in the microenvironment, shifting toward either IL-10+ or IL-17+ profiles. However, if such patterns are maintained in the context of inflammatory diseases is unknown. Here, we investigated MAIT cell functional plasticity in Crohn's disease (CD). Circulating MAIT cells in CD patients were impaired both in terms of numbers, and in terms of interferon γ (IFN-γ) and tumor necrosis factor (TNF) expression, and cytotoxic properties in response to MR1-presented antigen. However, the MAIT cell regulatory IL-10+ profile and the IL-17A+ profile were compromised only during active disease and relatively preserved during remission. Transcriptional analysis of intestinal T cells suggested that MAIT cells in CD displayed elevated GNLY and NKG7 expression, while transcripts associated with regulation and quiescence characterized MAIT cells in healthy donor control tissue. There were also distinct transcriptional signatures according to localization, where intra-epithelial MAIT cells exhibited a tissue resident regulatory profile, whereas those in the lamina propria showed signs of activation and recruitment. Finally, we assessed whether treatments for CD influenced MAIT cell functionality in vitro. Corticosteroids and upadacitinib inhibited MAIT cell activation, yet upadacitinib promoted increased GM-CSF and IL-17A expression in the context of combined antigen and IL-18 stimulation. These findings indicate that MAIT cell functional response patterns are influenced by CD disease stage, treatment, and tissue localization.