Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity.
Kishi Yasuhiro,Kondo Takaaki,Xiao Sheng,Yosef Nir,Gaublomme Jellert,Wu Chuan,Wang Chao,Chihara Norio,Regev Aviv,Joller Nicole,Kuchroo Vijay K
The Journal of experimental medicine
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 (PROCR) as a cell surface molecule expressed in covariance with the regulatory module of Th17 cells. Although PROCR expression in T cells was controlled by the cooperative action of the Th17 lineage-specific transcription factors RORγt, IRF4, and STAT3, PROCR negatively regulated Th17 differentiation. CD4 T cells from PROCR low expressor mutant mice readily differentiated into Th17 cells, whereas addition of the PROCR ligand, activated protein C, inhibited Th17 differentiation in vitro. In addition, PROCR 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 PROCR resulted in the exacerbation of experimental autoimmune encephalomyelitis (EAE) and higher frequencies of Th17 cell in vivo, indicating that PROCR also inhibits pathogenicity of Th17 cells in vivo. PROCR thus does not globally inhibit Th17 responses but could be targeted to selectively inhibit proinflammatory Th17 cells.
The many faces of Th17 cells.
Peters Anneli,Lee Youjin,Kuchroo Vijay K
Current opinion in immunology
Th17 cells have been shown to be strong inducers of tissue inflammation and autoimmune diseases. However, not all Th17 cells are pathogenic and increasing data suggest that Th17 cells may come in different flavors. Thus, Th17 cells cannot be described using a narrow schematic, but instead Th17 cells comprise a wide spectrum with a range of effector phenotypes. Here, we review the key factors that generate such diversity, as well as the cytokines and transcription factors that are differentially expressed in pathogenic and nonpathogenic Th17 cells. This new knowledge can be used to identify molecules that make Th17 cells pathogenic and determine how these cells could be targeted to suppress autoimmune diseases.