Th17/regulatory T cells balance is predictive of Coccidioides infection outcome in pediatric patients

Background: Protective immunity against the fungal pathogen Coccidioides requires specific T helper responses. Mouse vaccine and infection studies have defined CD4+ T helper (Th)1 and Th17 cells in the resolution of infection and in effective protection. Patients with persistent Coccidioides infection demonstrate reduced cellular responses. Methods: Peripheral blood and serum were collected from 30 pediatric Coccidioides-infected patients and 20 healthy controls in the California San Joaquin Valley. Samples were evaluated by flow cytometry for innate and adaptive immune populations and cytokines to define the early immune response and identify clinically useful biomarkers for predicting disease outcome. Clinical and flow data were evaluated according to disease outcome (resolved or persistent) using principal component analysis, high-dimensional flow cytometry analysis tools, chi-square automatic interaction detection, and individual cell population comparisons. Results: Patients with persistent infection had lower Th17 and higher Treg frequencies, but similar Th1 responses, relative to patients that resolved disease. Treg frequency, eosinophil numbers and neutrophil numbers together distinguish patients that resolve infection from those that develop persistent infection. Conclusions: The inability to resolve Coccidioides infection may be a result of elevated Treg frequency and functional capacity, and Treg frequency may predict patient disease outcome at diagnosis. In our study, Th1 responses were similar in persistent and resolved infection, in contrast to prior human studies. Instead, our data suggest that Th17 cells provide an effective protection during Coccidioides infection, and that elevated Treg frequency inhibits protective immunity.