Defining MHC class I restricted antigen presentation to CD8 T cells in experimental AD and Tauopathy

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ABSTRACT - Alzheimer’s disease (AD) and other neurodegenerative conditions are characterized by heightened inflammation, neurodegeneration, and CNS vascular permeability, including microhemorrhage formation. The role of specific immune cell types in the underlying neuropathology associated with AD and other neurologic diseases remains an active area of research. Significant attention has been given to the role of innate immune cells and microglia in the development of AD. However, the role of adaptive immune cells, including CD8 T cells, has not been defined despite their presence in brain parenchyma of AD patients. These findings were further accentuated by the recent analysis of CD8 T cell repertoire and correlation with disease severity in human AD patients. APP/PS1 mice revealed significant brain infiltration of CD8 T cells of effector phenotype. Similarly, our Co-investigator, Dr. John Fryer of Mayo Clinic Arizona, has also observed significant CD8 T cell brain infiltration in his novel rAAV initiated tauopathy mouse model. Using our novel MHC class I conditional knockout mice, we have determined that macrophages and dendritic cells prime non-equivalent CD8 T cell responses in response to PbA infection. While both antigen presenting cells prime CD8 T cell response that infiltrate the brain, only CD8 T cells raised by dendritic cells induce lethal blood-brain barrier disruption. Our central hypothesis that clonally expanded CD8 T cells engage brain vasculature and migratory antigen presenting cells during infiltration which contributes to neuropathology and cognitive deficits in AD and Tauopathies. We plan to test this central hypothesis through execution of the following specific aims: Specific Aim 1 – Define the CD8 T cell repertoire and phenotype(s) generated in APP/PS1 and Tauopathy mice through transcriptional profiling. Specific Aim 2 – Determine critical role of residential and migratory APCs in priming and enabling CNS infiltration of CD8 T cell responses in APP/PS1 and Tauopathy mouse models Specific Aim 3 – Dissect the critical MHC class I expressing CNS cell type required for CD8 T cell induced neuropathology and cognitive deficits The proposed work is innovative because it capitalizes on our unique transgenic mouse models, novel imaging methodology, and new core facilities available to our research program at Mayo Clinic. Our goal is to define mechanistically the contribution of CD8 T cells in human dementia through knowledge gained using leading experimental models. Beyond the innovative methodology employed, the concept that antigen presenting cells raise differential CD8 T cell responses is highly novel and warrants further investigation to a mechanism which is therapeutically targetable. This is especially important if CD8 T cell priming and engagement of antigen presented by specific cell types is promoting neuropathology and behavioral deficits.