Background/Purpose: Mucosal-associated invariant T (MAIT) cells represent a specialized subset of T cells that exhibit innate-like, effector functions and have been implicated in the pathogenesis of several autoimmune disorders, including IL-17-driven diseases such as ankylosing spondylitis and hidradenitis suppurativa. MAIT cells are activated through recognition of microbial and self-metabolites presented by MR1, a non-polymorphic, MHC class I-like molecule. Upon activation, they amplify inflammation by producing pro-inflammatory cytokines (e.g., IFN-γ, TNF-α) and cytotoxic molecules such as perforin and granzyme B. Notably, MAIT cells are a potent source of IL-17A and IL-17F.

Methods: In this study, we investigated the requirement for IL-23 and TL1A, known Th17 driving cytokines, in regulating IL-17 production by MAIT cells. Using human peripheral blood mononuclear cells (PBMCs), we validated that proagent of 5-A-RU (p5-A-RU), a known MR1 ligand, specifically activates MAIT cells, as indicated by the selective upregulation of CD69 within the MAIT cell population. This activation was dependent on antigen-presenting cells (APCs), as depletion of monocytes and B cells abolished CD69 expression on MAIT cells.

Results: Furthermore, we demonstrated that p5-A-RU synergizes with IL-12 and IL-18 to drive the production of inflammatory effector molecules, including perforin, granzyme B, TNF-α, IFN-γ, and IL-17. Interestingly, IL-17A and IL-17F production was not enhanced by exogenous IL-23, nor was it reduced by the application of clinically validated neutralizing antibodies against these cytokines. In contrast, MR1 blockade completely abrogated MAIT cell activation in both PBMCs and human skin explants. Previous work has shown that MAIT cells play a significant role in tissue repair. To explore the potential role of MAIT cells in tissue repair, we assessed the effect of conditioned media from activated MAIT cells on wound healing in vitro using primary human lung fibroblasts. No enhancement in wound repair was observed, suggesting that inflammatory MAIT cells may not contribute to tissue regeneration.

Conclusion: Collectively, our findings highlight a key role for IL-12 and IL-18 in driving IL-17A and IL-17F production by MAIT cells, independently of IL-23 and TL1A. This MR1-dependent activation pathway could represent a novel therapeutic target, particularly for IL-17-mediated autoimmune diseases such as ankylosing spondylitis and hidradenitis suppurativa.

« Back to ACR Convergence 2025

ACR Meeting Abstracts - https://acrabstracts.org/abstract/human-mait-cell-produce-il-17-independently-of-il-23-and-tl1a/