Background <p>The role of immune cells in neurodegeneration remains incompletely understood. Accumulation of misfolded tau proteins is a hallmark of neurodegenerative diseases. 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. However, the role of MAIT cells in tau-related neuroinflammation and neurodegeneration remains unknown.</p> Methods <p>Flow cytometry analysis was performed to examine MAIT cells in human Tau P301S transgenic mice. Tau pathology, hippocampus atrophy, meningeal integrity, and microglial gene expression were examined in <i>Mr1</i>^{<i>−/−</i>} P301S mice that lacked MAIT cells and control P301S transgenic mice, as well as <i>Mr1</i>^{<i>−/−</i>} P301S mice with adoptive transfer of MAIT cells.</p> Results <p>The meninges of P301S mutant human tau transgenic mice had increased numbers of MAIT cells, which retained their expression of antioxidant molecules. <i>Mr1</i>^{<i>−/−</i>}<i>P301S</i> mice that lacked MAIT cells exhibited increased tau pathology and hippocampus atrophy compared to control <i>Mr1</i>^+/+P301S mice. Adoptive transfer of MAIT cells reduced tau pathology and hippocampus atrophy in <i>Mr1</i>^{<i>−/−</i>} P301S mice. Meningeal barrier integrity was compromised in <i>Mr1</i>^{<i>−/−</i>}P301S mice, but not in control <i>Mr1</i>^+/+P301S mice. A distinctive microglia subset with a proinflammatory gene expression profile (M-inflammatory) was enriched in the hippocampus of <i>Mr1</i>^{<i>−/−</i>}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 to ribosome biogenesis and immune responses to toxic substances. The transfer of MAIT cells restored meningeal barrier integrity and suppressed microglial inflammation in the <i>Mr1</i>^{<i>−/−</i>}<i> P301S</i> mice.</p> Conclusions <p>Our data indicate an important role for MAIT cells in regulating tau-pathology-related neuroinflammation and neurodegeneration.</p>