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 molecu...

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Published inThe Journal of experimental medicine Vol. 213; no. 11; pp. 2489 - 2501
Main Authors Kishi, Yasuhiro, Kondo, Takaaki, Xiao, Sheng, Yosef, Nir, Gaublomme, Jellert, Wu, Chuan, Wang, Chao, Chihara, Norio, Regev, Aviv, Joller, Nicole, Kuchroo, Vijay K.
Format Journal Article
LanguageEnglish
Published United States The Rockefeller University Press 17.10.2016
Subjects
Animals
Cell Differentiation - immunology
Endothelial Protein C Receptor
Gene Expression Profiling
Inflammation - genetics
Inflammation - pathology
Mice, Inbred C57BL
Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism
Promoter Regions, Genetic - genetics
Protein Binding
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Receptors, Interleukin - metabolism
Receptors, Interleukin-1 - metabolism
STAT3 Transcription Factor - metabolism
Th17 Cells - immunology
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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 (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.
AbstractList 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.
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.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.
Kishi et al. find that protein C receptor (PROCR) is specifically expressed on the surface of Th17 cells and its loss exacerbates encephalitogenic Th17 cell responses. 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.
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.
Author Gaublomme, Jellert
Chihara, Norio
Joller, Nicole
Wu, Chuan
Wang, Chao
Kishi, Yasuhiro
Kuchroo, Vijay K.
Regev, Aviv
Kondo, Takaaki
Xiao, Sheng
Yosef, Nir
AuthorAffiliation 4 Institute of Experimental Immunology, University of Zurich, 8006 Zurich, Switzerland
3 Broad Institute of MIT and Harvard, Cambridge, MA 02142
2 Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho 1000, Yokohama 227-0033, Japan
1 Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115
AuthorAffiliation_xml – name: 3 Broad Institute of MIT and Harvard, Cambridge, MA 02142
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– name: 4 Institute of Experimental Immunology, University of Zurich, 8006 Zurich, Switzerland
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N. Joller and V.K. Kuchroo contributed equally to this paper.
Y. Kishi and T. Kondo contributed equally to this paper.
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Snippet Th17 cells are key players in defense against pathogens and maintaining tissue homeostasis, but also act as critical drivers of autoimmune diseases. Based on...
Kishi et al. find that protein C receptor (PROCR) is specifically expressed on the surface of Th17 cells and its loss exacerbates encephalitogenic Th17 cell...
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StartPage 2489
SubjectTerms Animals
Cell Differentiation - immunology
Endothelial Protein C Receptor
Gene Expression Profiling
Inflammation - genetics
Inflammation - pathology
Mice, Inbred C57BL
Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism
Promoter Regions, Genetic - genetics
Protein Binding
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Receptors, Interleukin - metabolism
Receptors, Interleukin-1 - metabolism
STAT3 Transcription Factor - metabolism
Th17 Cells - immunology
Title Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity
URI https://www.ncbi.nlm.nih.gov/pubmed/27670590
https://www.proquest.com/docview/1835529326
https://pubmed.ncbi.nlm.nih.gov/PMC5068226
Volume 213
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