CD15+ Myeloid Cells from Patients with Disseminated Coccidioidomycosis Inhibit CD4+ T Cell Proliferation 2260247

Abstract

Abstract Introduction Valley fever (VF) is a respiratory disease caused by Coccidioides and is estimated to cost over 3 billion in medical costs annually. In VF, the infiltration of Ly6G+ cells into the lungs has been reported in mice and humans, but the role of these cells has not been fully uncovered. Ly6G+ cells share a phenotype with myeloid-derived suppressor cells (MDSCs), which suppress protective immunity. We previously showed, Ly6G+ cells enriched from the lungs of non-protected mice suppressed CD4+ T cell proliferation and exacerbated disease in vaccinated mice. Thus, a portion of the infiltrated Ly6G+ cells comprises MDSCs, which contribute to the pathogenesis. Parallelly, we have analyzed PBMCs from VF patients, to investigate whether these myeloid cells are immunosuppressive. We hypothesize CD15+ cells isolated from the PBMCs of disseminated patients suppress CD4+ T cell function to a greater extent than those isolated from recovered patients. Methods PBMCs from recovered (n = 18), pulmonary (n = 5), and disseminated (n = 11) VF patients were evaluated for CD15 + (HLA-DR-CD11b+CD15+). A functional assay was performed in recovered (n = 10), pulmonary (n = 4), and disseminated (n = 6) patients. CD15+ cells were enriched and combined with autologous CD4+ T cells at a 1:1 ratio with anti-CD3/CD28 beads for 72 hours. Results Flow cytometric analysis revealed that the composition of CD15+ myeloid cells in PBMCs from three patient cohorts was comparable, consistent with other reports of microbial infection. Indeed the CD15+ cells from disseminated patients suppressed a significantly higher percentage of CD4+ T cell proliferation than those from recovered and pulmonary patients. Conclusion These data demonstrate that CD15+ myeloid cells from disseminated patients suppress CD4+ T cells, a function shared with MDSCs. This discovery is parallel to our previous report that MDSCs are recruited into the lungs and exacerbate disease in Coccidioides-infected mice. Our data provide an insight on the role of CD15+ myeloid cells in VF. Funding Source The National Institute of Allergy and Infectious Diseases, National Institutes of Health, provided funding for this research under grants R01 AI135005 (CYH), U19AI166761 (CYH), and training grant T32AI184340 (RN and MMB). Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)