Mouse CD11b+Gr-1+ myeloid cells can promote T helper 17 cell differentiation and experimental autoimmune encephalomyelitis

摘要

Myeloid-derived suppressive cells (MDSCs) have been a focus of recent study on tumor-mediated immune suppression. However, its role in type 17 helper T (Th17) cell differentiation and the pathogenesis of autoimmune diseases (e.g., multiple sclerosis) has not been determined. We show here that development of experimental autoimmune encephalomyelitis (EAE) in mice is associated with a profound expansion of CD11b⁺Gr-1⁺ MDSCs, which display efficient T cell inhibitory functions in vitro. Unexpectedly, these MDSCs enhance the differentiation of naïve CD4⁺ T cell precursors into Th17 cells in a highly efficient manner under Th17 polarizing conditions, as indicated by significantly increased number of Th17 cell, elevation of IL-17A production, and upregulation of the orphan nuclear receptor RORA and RORC. Mechanistic studies show that IL-1β represents a major mediator of MDSC-facilitated Th17 differentiation, which depends on the IL-1 receptor on CD4⁺ T cells but not MDSCs. Selective depletion of MDSCs using gemcitabine results in a marked reduction in the severity of EAE (e.g., decreased clinical scores and myelin injury), which correlates with reduced Th17 cells and inflammatory cytokines (IL-17A and IL-1β) in the lymphoid tissues and spinal cords. Adoptively transfer of MDSCs after gemcitabine treatment restores EAE disease progression. Together, we demonstrate for the first time that excessive and prolonged presence of MDSCs can drive a Th17 response and consequently contributes to the pathogenesis of EAE. These new findings provide unique insights into the pleiotropic functions of MDSCs, and may help explain the failure of immunosuppressive MDSCs to control Th17/IL-17-dependent autoimmune disorders.