Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity.
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.
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.|Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho 1000, Yokohama 227-0033, Japan.
Yasuhiro
0000-0003-3550-915X
Y
Kishi
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.|Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho 1000, Yokohama 227-0033, Japan.
Takaaki
T
Kondo
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
Sheng
0000-0001-6252-8204
S
Xiao
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.|Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Nir
0000-0001-9004-1225
N
Yosef
Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Jellert
0000-0002-1266-052X
J
Gaublomme
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
Chuan
C
Wu
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
Chao
C
Wang
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
Norio
N
Chihara
Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Aviv
A
Regev
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115 vkuchroo@evergrande.hms.harvard.edu nicole.joller@immunology.uzh.ch.|Institute of Experimental Immunology, University of Zurich, 8006 Zurich, Switzerland.
Nicole
0000-0003-1996-1672
N
Joller
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115 vkuchroo@evergrande.hms.harvard.edu nicole.joller@immunology.uzh.ch.|Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Vijay K
0000-0001-7177-2110
VK
Kuchroo
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D000074283:Endothelial Protein C Receptor; D020869:Gene Expression Profiling; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008810:Mice, Inbred C57BL; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology*
D000074283:Endothelial Protein C Receptor; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C080248:Procr protein, mouse; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D050796:STAT3 Transcription Factor; C528688:interleukin-23 receptor, mouse
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