bims-maitce 2025-01-19 papers

Issue of 2025–01–19
two papers selected by
Andy E. Hogan, Maynooth University

bioRxiv. 2025 Jan 03. pii: 2025.01.03.631124. [Epub ahead of print]

MAIT cell deficiency exacerbates neuroinflammation in P301S human tau transgenic mice.

Yuanyue Zhang, Zhi Yang, Xiaosheng Tan, Na Jiang, Gaoyuan Cao, Qi Yang.

The role of immune cells in neurodegeneration remains incompletely understood. Our recent study revealed the presence of mucosal-associated invariant T (MAIT) cells in the meninges, where they express antioxidant molecules to maintain meningeal barrier integrity. Accumulation of misfolded tau proteins are a hallmark of neurodegenerative diseases. The role of MAIT cells in tau-related neuroinflammation and neurodegeneration, however, remains unclear. Here we report that the meninges of P301 mutant human tau transgenic mice had increased numbers of MAIT cells, which retained their expression of antioxidant molecules. Mr1 -/- P301S mice that lacked MAIT cells exhibited increased tau pathology and hippocampus atrophy compared to control Mr1 +/+ P301S mice. Adoptive transfer of MAIT cells reduced tau pathology and hippocampus atrophy in Mr1 -/- P301S mice. Meningeal barrier integrity was compromised in Mr/ -/- P301S mice, but not in control Mr1 +/+ P301S mice. A distinctive microglia subset with proinflammatory gene expression profile (M-inflammatory) was enriched in the hippocampus of Mr1 -/- P301S mice. The transcriptomes of the remaining microglia in these mice also shifted towards a proinflammatory state, with increased expression of inflammatory cytokines, chemokines, and genes related with ribosome biogenesis and immune responses to toxic substances. The transfer of MAIT cells restored meningeal barrier integrity and suppressed microglial inflammation in the Mr1 -/- P301S mice. Together, our data indicate an important role for MAIT cells in regulating tau-pathology-related neuroinflammation and neurodegeneration.

DOI: https://doi.org/10.1101/2025.01.03.631124

J Exp Med. 2025 Feb 03. pii: e20240896. [Epub ahead of print]222(2):

Cigarette smoke components modulate the MR1-MAIT axis.

Tobacco smoking is prevalent across the world and causes numerous diseases. Cigarette smoke (CS) compromises immunity, yet little is known of the components of CS that impact T cell function. MR1 is a ubiquitous molecule that presents bacterial metabolites to MAIT cells, which are highly abundant in the lungs. Using in silico, cellular, and biochemical approaches, we identified components of CS that bind MR1 and impact MR1 cell surface expression. Compounds, including nicotinaldehyde, phenylpropanoid, and benzaldehyde-related scaffolds, bound within the A' pocket of MR1. CS inhibited MAIT cell activation, ex vivo, via TCR-dependent and TCR-independent mechanisms. Chronic CS exposure altered MAIT cell phenotype and function and attenuated MAIT cell responses to influenza A virus infection in vivo. MR1-deficient mice were partially protected from the development of chronic obstructive pulmonary disease (COPD) features that were associated with CS exposure. Thus, CS can impair MAIT cell function by diverse mechanisms, and potentially contribute to infection susceptibility and disease exacerbations.

DOI: https://doi.org/10.1084/jem.20240896