Abstract Disseminated coccidioidomycosis (DCM) can be explained by a combination of defective host defenses and successful immune evasion by the fungus. Published data from our labs highlight the importance of T cells in fighting fungal infections, and in going awry in disseminated disease. Our main goal is to discover the T cell patterns and programs that mediate dysfunction and allow for invasive coccidioidomycosis. T-cell activation requires the antigens of the pathogen to be presented, and this process offers an opportunity for adaptive immunity to founder. Major histocompatibility complex (MHC) subtypes, commonly also called HLA alleles, have been shown to play an important role in susceptibility to severe infection, including coccidioidomycosis, because these molecules present antigenic peptides to T cells. Which HLA alleles contribute to susceptibility has not been studied in over 20 years, and modern approaches including those published by our team shed considerably more light on the antigen presentation process. Importantly, which peptides are important for protection to coccidioidomycosis is as yet unknown. Our approach data includes a new technology to empirically discover those key peptides of Coccidioides. In Aim 1, we will discover the antigenic peptides, HLAs, and T-cell receptors that mediate DCM. Upon T-cell activation, transcriptional programs arise as cued by cytokines of the antigen presenting cells. Our published and preliminary data support that T-cell dysfunction underlies the defective immune responses of DCM. These aberrant responses may arise either due to genetic or epigenetic defects of the T cell program, which may be due to rare or common genetic variants or haplotype variants associated with genetic ancestry. These aberrant responses could also be due to abnormal skewing due to cytokines made by APCs. Clearance of pathogens within a few days is requisite, or else persistent antigen exposure drives T cells to a profound phenotypic switch that includes physical elimination of antigen-specific T cells, driving them to a state of antigen- unresponsiveness, or driving them to a state of senescence. Our preliminary data support that in subjects with DCM, T cells exhibit both an exhaustion and senescence phenotype. In Aim 2, we will first take an unbiased approach to discover transcriptional patterns that highlight DCM versus UVF. We will pursue single-cell RNA- seq and scATAC-seq to identify cells and patterns of transcription that correlate with disease. We will study subjects with DCM who bear the markers of the three dysfunctional programs above with this approach. These studies will enable discovery of the various subcategories of DCM patients and the functional deficiencies in their T cells.