Exhausted T cell phenotypes in disseminated coccidioidomycosis

Coccidioidomycosis presents clinically as a spectrum ranging from self-limiting Uncomplicated Valley Fever (UVF) in most cases to life-threatening Disseminated Coccidioidomycosis (DCM) in rare individuals. A few patterns of immunologic deficits allowing for dissemination have been identified, though the specific defects in most individuals with DCM remain undefined. We hypothesized that chronic antigen exposure in DCM engenders a state of T cell exhaustion. From a cohort of over 300 subjects with confirmed diagnoses of coccidioidomycosis, circulating T cell phenotypes were characterized via flow cytometry and <i>Coccidioides</i>-specific T cell responses were measured using the Activation-Induced Marker (AIM) assay. Male sex was significantly associated with disseminated disease (odds ratio 2.5; 95% CI: 1.5 - 4.0). 52% of subjects showed Coccidioides-specific T cell responses in our AIM assay. We noted a significant difference in subjects sampled in the first year of diagnosis, where only 8% of DCM subjects had T cell responses during this time, as compared to 44% of UVF subjects (p = 0.04). Among DCM patients with detectable AIM responses, CD4+ T cells demonstrated an exhausted phenotype with elevated PD-1 expression compared to UVF subjects. In vitro PD-1 blockade augmented IFNγ production in most tested DCM subjects. These findings suggest that dissemination may occur in some individuals during a period of impaired antigen-specific T-cell activity. Importantly, these responses can be augmented in vitro by PD-1 blocking antibodies, supporting further study of immune checkpoint therapy as an adjunct to antifungal treatment in disseminated coccidioidomycosis.