Project Summary/Abstract Alzheimer’s disease and the related disorder Frontotemporal dementia (FTD) represent a major financial and emotional burden to society, but to date no preventative strategies have been developed. While a critical barrier to improving the quality of life for people suffering from or caring for those with FTD is a lack of mechanistic understanding of the causes, there is substantial evidence that T cell dysfunction and the balance of T cell subsets contributes to disease pathogenesis and may explain heterogenous patient outcomes. This suggests that strategies to stabilize patient T regulatory cells and/or reduce levels of pro-inflammatory Th17 cells are likely to benefit FTD patients. A key knowledge gap is how environmental signals such as those derived from the gut microbiome interact with common FTD genotypes to affect T cell function and disease progression. A repeat expansion in a non-protein-coding region of the gene C9ORF72 is the most common cause of FTD and the related motor neuron disorder Amyotrophic lateral sclerosis, responsible for approximately 10% of all diagnoses. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration. The expansion is transcribed into a long repetitive RNA that sequesters RNA binding proteins before being translated into aggregate-prone repetitive dipeptide proteins. The mutation also leads to reduction of the endogenous C9ORF72 gene product that functions in endo-lysosomal pathways and suppresses systemic and neural inflammation. In preliminary work, we have demonstrated that signals derived from gut bacteria modify the penetrance and expressivity of neural inflammation in mice with reduction of C9orf72. Additionally, we have established that C9orf72 functions in cells of both the myeloid and lymphoid lineages to oppose autoimmunity and neural inflammation. The first AIM of this proposal will seek to elucidate how C9orf72 functions within T cells to govern cell fate choice. The second AIM of this proposal will seek to determine how a C9orf72 genotype influences pathogenic T cell responses to intestinal microbes and to determine the extent to which pro-inflammatory cytokine Interleukin-17A participates in neural inflammation when C9orf72 levels decline. In the third AIM of this proposal, we will evaluate whether the changes in T cell fate and function we observe in our animal model also occur in humans with a C9ORF72 mutation that converts to FTD but not in carriers of the mutation that are protected from neurological disease. The proposed studies have potential to shed mechanistic insight into regulation of FTD/ALS disease course by T cells and to identify novel prognostic markers and therapeutic targets for Alzheimer’s disease and related dementias.