Mucosal-associated invariant T (MAIT) cells are a major subset of human innate-like T cells enriched in barrier tissues. They detect microbial infections by recognising riboflavin-derived metabolites and have been extensively studied in the context of bacterial infections. However, despite fungi being capable of producing MAIT cell antigens, their role in antifungal immunity remains undefined. Aspergillus fumigatus, a ubiquitous environmental mould, causes life-threatening opportunistic infections in humans and is classified by the WHO as a top-priority fungal pathogen due to its high mortality, increasing incidence, and emerging antifungal resistance. It has been shown that Aspergillus can activate human MAIT cells in an MR1-dependent manner. Here, we use mouse models of systemic and pulmonary Aspergillus infection to investigate the antifungal functions of MAIT cells.
We found that systemic Aspergillus infection led to robust MAIT cell expansion across multiple tissues, including the kidneys and brain—organs typically affected during invasive aspergillosis. This expansion was dependent on MR1-mediated antigen presentation but, unexpectedly, was impaired by administration of the synthetic MAIT cell antigen 5-OP-RU. The responding MAIT cells predominantly originated from canonical T-bet⁺ MAIT1 cells and exhibited a Th1-skewed cytokine profile, while also producing IL-4 and low but detectable levels of IL-10. Both Mr1-/- and Traj33-/- mouse strains, which are deficient in MAIT cells, showed similar elevated fungal burdens compared to wild-type controls, supporting a protective role for MAIT cells during fungal infection. This protection was independent of neutrophils, whose deficiency is a major risk factor for Aspergillus infection. Moreover, adoptive transfer of MAIT cells into immunodeficient Rag2-/-γC-/- mice improved fungal control, highlighting their therapeutic potential.
In summary, our data define a protective role for MAIT cells in host defence against A. fumigatus and support their potential clinical application in immunodeficient patients with invasive infection.