Myeloid-derived suppressor cell (MDSC)-like neutrophils induced by pulmonary infection with Coccidioides posadasii exacerbate disease by suppressing CD4 + T cell immunity

ABSTRACT Coccidioidomycosis is a pulmonary disease caused by the dimorphic fungus Coccidioides , which is endemic to the southwestern United States and South America. Coccidioides grows as septate hyphae in soil and forms spores that can become airborne during mechanical disruption of the soil. In the lungs, the inhaled spores develop into large multinucleated spherules, a unique morphology among medically important Coccidioides species, and reproduce by endosporulation. A hallmark of the host immune response toward endosporulating spherules is the robust recruitment and infiltration of Ly6G + neutrophils. However, the effectiveness of Ly6G + neutrophils against Coccidioides remains to be studied. Myeloid-derived suppressor cells (MDSCs) are immunosuppressive and share an origin and many phenotypic features with neutrophils. Here, we demonstrated that Ly6G + cells, but not Ly6C + cells, increased lung expression of the inhibitory programmed death-ligand 1 (PD-L1) in diseased mice. The Ly6G + PD-L1 + cells share common characteristics of granulocytic MDSCs. Bone-marrow-derived GR-1 + myeloid cells, including both Ly6G + and Ly6C + cells, suppressed the proliferation of CD4 + T cells after exposure to spherules. Furthermore, isolated GR-1 + cells from the lungs and spleens of Coccidioides -infected non-protected mice also suppressed CD4 + T cell proliferation, thereby diminishing adaptive T cell responses. Adoptive transfer of GR-1 + myeloid cells isolated from the lungs of Coccidioides -infected mice, or derived from bone marrow exposed to paraformaldehyde-killed spherules, into vaccine-protected recipients exacerbated coccidioidomycosis through the reduction of protective Th1 and Th17 responses. Altogether, we demonstrate that pulmonary infiltration of MDSC-like neutrophils, in non-vaccinated mice, play a detrimental role in coccidioidomycosis by inhibiting protective CD4 + T cell responses. IMPORTANCE Dimorphic fungi are primary pathogens that infect both immunocompetent and immunocompromised hosts. Fungal pathogens have evolved sophisticated strategies to evade innate immune responses, which have not been well studied. Recently, myeloid-derived suppressor cells (MDSCs) have been described in the pathogenesis of several fungal infections, including Candida albicans and Cryptococcus neoformans . Here, we use a live-attenuated vaccine model to investigate the role of Ly6G + myeloid cells during Coccidioides infection in mice. We have shown that pulmonary Coccidioides posadasii infection leads to the accumulation of programmed death-ligand 1 (PD-L1) + Ly6G + MDSC-like neutrophils that suppress CD4 + T cell proliferation and exacerbate disease by reducing protective Th1 and Th17 responses. Moreover, adoptive transfer of GR-1 + myeloid cells isolated from Coccidioides -infected mice into vaccine-protected recipient mice reduced protective efficacy by increasing fungal burden and disease severity. Our data suggest that immunosuppressive Ly6G + PD-L1 + MDSC-like neutrophils play a detrimental role by suppressing protective T cell responses in pulmonary Coccidioides infection.