Type-2 immune skewing in patients with disseminated coccidioidomycosis.

Background: Disseminated coccidioidomycosis (DCM) is an often fatal and otherwise intractable condition requiring lifelong antifungal treatment. We have previously shown that a deranged polarization of CD4 ⁺ T cells toward a Type-2 phenotype can exist in the context of DCM. Here we studied a large population of subjects to determine the frequency of abnormal Type-2 skewing of CD4 ⁺ T cells in patients with coccidioidomycosis and to identify underlying genetic mechanisms supporting this skew.

Methods: We collected peripheral blood mononuclear cells from 204 patients with coccidioidomycosis, including 96 patients with disseminated disease. We measured immune phenotypes and cytokine production by CD4 ⁺ T cells from patients and healthy controls, and comparisons between groups were made based on disease severity and demographics. Whole genome sequencing was conducted on 149 individuals who also had cytokine profiling.

Results: We found that ~20% of DCM patients had a CD4 ⁺ T-cell compartment that was abnormally skewed toward a Type-2 (IFN-γ-IL-4+) phenotype. Type-2 skewing was highly correlated with male sex, with 80% of moderately skewed (Th2:Th1 ratio > 1.5) and 100% of severely skewed (Th2:Th1 ratio > 2) patients being male. Co-culture of T cells with the IL4R/IL13R-blocking antibody dupilumab rectified their Th1/Th2 skewing. Sequencing revealed rare variants in genes involved in the IL-12-IFN-γ axis in several Type-2 skewed patients, and we validated one such variant in IFNGR1 as hypomorphic.

Conclusion: Patients with DCM, especially those who are male, should be screened for Type-2 skewing of CD4 ⁺ T cells. Patients with Type-2 skewing should be additionally screened for genetic defects in the IL-12-IFN-γ axis. Our findings give a mechanistic rationale for exploring blockade of IL4R as a treatment option in Type-2 skewed patients with refractory coccidioidomycosis.