Protein C receptor (PRO CR) is a negative regulator of Th17 pathogenicity

Abstract

Th17 cells are key players in defense against pathogens and maintaining tissue homeostasis, but also act as critical drivers of autoimmune diseases. Based on single-cell RNA-seq profiling of pathogenic versus nonpathogenic Th17 cells, we identified protein C receptor (PRO CR) as a cell surface molecule expressed in covariance with the regulatory module of Th17 cells. Although PRO CR expression in T cells was controlled by the cooperative action of the Th17 lineage-specific transcription factors RORγt, IRF4, and STAT3, PRO CR negatively regulated Th17 differentiation. CD4+ T cells from PRO CR low expressor mutant mice readily differentiated into Th17 cells, whereas addition of the PRO CR ligand, activated protein C, inhibited Th17 differentiation in vitro. In addition, PRO CR acted as a negative regulator of Th17 pathogenicity in that it down-regulated expression of several pathogenic signature genes, including IL-1 and IL-23 receptors. Furthermore, T cell-specific deficiency of PRO CR resulted in the exacerbation of experimental autoimmune encephalomyelitis (EAE) and higher frequencies of Th17 cell in vivo, indicating that PRO CR also inhibits pathogenicity of Th17 cells in vivo. PRO CR thus does not globally inhibit Th17 responses but could be targeted to selectively inhibit proinflammatory Th17 cells.