Oral Presentation CD1-MR1 2024

Plasticity of MAIT17 cells contributes to MAIT cell protective immunity. (#60)

Huimeng Wang 1 2 , Michael NT Souter 1 , Marcela de Lima Moreira 1 , Yuchen Zhou 1 3 , Adam G Nelson 1 , Lucy J Meehan 1 , Xin Yi Lim 1 , Bronwyn S Meehan 1 , Sidonia BG Eckle 1 , Ashraful Haque 1 , Jeffrey YW Mak 4 5 , David P Fairlie 4 5 , James McCluskey 1 , Zhongfang Wang 2 , Zhenjun Chen 1 , Alexandra J Corbett 1
  1. Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia
  2. State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong, China
  3. School of Medicine, Tsinghua University, Beijing, China
  4. Division of Chemistry and Structural Biology, The University of Queensland, Brisbane, QLD, Australia
  5. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, QLD, Australia

Mucosal-associated invariant T (MAIT) cells recognize microbial metabolite-based antigens and provide protection against bacterial pathogens. During thymic development, mouse MAIT cells commit to two major subpopulations with distinct tissue tropism and effector functions, namely, T-bet-expressing MAIT1 or RORγt-expressing MAIT17 cells. This early commitment allows mature MAIT cells to serve as rapid responders to specific threats. However, a key question is whether MAIT cells are rigidly fixed in their identities, or if they can convert between subsets, or transdifferentiate into new subsets beyond their initial commitment.

In this study, we utilized reporter and fate-mapping mice to examine the plasticity of MAIT1 and MAIT17 cells across a range of MAIT cell expansion and infection models. We found that RORγt+T-bet-MAIT17 cells were highly plastic, with capability to undergo phenotypic and functional conversion into both RORγt+T-bet+ MAIT1/17 and RORγt-T-bet+MAIT1 cells after acute infection, or even under homeostatic conditions. In contrast, MAIT1 cells remained stable in all experimental settings. The relative contribution of MAIT17 cells to the type 1 MAIT cell response against infections varied between tissues and was particularly apparent in mucosal sites where MAIT1 cells were typically absent. scRNA-seq analysis revealed that MAIT17-derived MAIT1 cells were distinct from canonical MAIT1 cells at the transcriptomic level. These MAIT17-derived MAIT1 cells were not in a transient state; rather, they could migrate out of mucosal tissues, contribute to the global MAIT1 pool, and help to combat subsequent systemic infections. Importantly, human MAIT cells also exhibit different functional subsets based on their cytokine production. Here, we demonstrated a similar plasticity of IL-17A-secreting human MAIT cells, revealing their capacity to shift towards IFN-γ production following polarizing stimulation. In summary, our findings offer direct evidence for the functional plasticity of MAIT cells, with potential therapeutic implications.