MR1/MAIT cell axis-mediated regulation of inflammatory responses - Alzheimer’s disease (AD) is a rapidly growing and serious worldwide malady, which is currently the most common cause of dementia in patients of advanced age. A major contributor to the brain pathology that is observed in AD patients is neuroinflammation, of which innate immunity plays a critical role. One component of the innate immune response that we have found contributes to AD is the MR1/MAIT cell axis. MR1 is a major histocompatibility complex class I-like molecule that is recognized by an invariant T cell subpopulation called, “mucosal-associated invariant T (MAIT) cells”. Notably, we have reported the presence of MAIT cell in the normal mouse brain. MAIT cells are innate-like T cells that have highly pathogenic roles in several different disease states, including some CNS disorders, via their production of the highly proinflammatory cytokine, IL-17A. We have detected increased MR1 expression in the temporal cortex of both AD patients and 8-month-old 5XFAD (AD model) mice and in their brain microglia as well. In fact, those microglia closer to and touching Aβ plaques have higher levels of MR1 than those further away and not touching. Moreover, we have found that there is a significantly greater number of MAIT cells in the brains and livers of 5XFAD vs. wildtype mice as they age. Importantly, crossing MR1-deficient mice (which have neither MR1 nor MAIT cells) onto the 5XFAD background, results in significantly delayed Aβ plaque development in the temporal cortex and hippocampus as compared to normal 5XFAD mice. Considering the variety of studies that have reported the substantial disease in AD patients and the various AD mouse models that have been studied to date, along with the associated neuroinflammation/neuroimmunopathology in the brain, we are focused on advancing our understanding the role of MR1 expression and MAIT cells in AD pathology development, using our preliminary data as a springboard to that end. Our hypothesis is that MAIT cell recognition of microglial and/or astrocyte MR1 results in MAIT cell production of IL-17A. This critically contributes to AD pathology upon the infiltration and/or proliferation of MAIT cells in the brain, resulting in significant neuroinflammation. To address this hypothesis, we have proposed the following three Specific Aims: 1. Determine the importance of brain microglial and astrocyte MR1 in AD pathology; 2. Define the contribution of IL-17A in MR1/MAIT cell-dependent AD development; 3. Determine the impact of MAIT cell numbers in AD neuroimmunopathology. These studies will allow us to determine mechanistic contributions of the MR1/MAIT cell axis in AD development in more detail, using both mouse models and AD patient tissue samples. This work could lead to the development of novel therapeutic approaches that target the MR1/MAIT cell axis in AD.
