CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity

Chao Wang; Nir Yosef; Jellert Gaublomme; Chuan Wu; Youjin Lee; Clary B Clish; Jim Kaminski; Sheng Xiao; Gerd Meyer Zu Horste; Mathias Pawlak; Yasuhiro Kishi; Nicole Joller; Katarzyna Karwacz; Chen Zhu; Maria Ordovas-Montanes; Asaf Madi; Ivo Wortman; Toru Miyazaki; Raymond A Sobel; Hongkun Park; Aviv Regev; Vijay K Kuchroo

doi:10.1016/j.cell.2015.10.068

CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity

Cell. 2015 Dec 3;163(6):1413-27. doi: 10.1016/j.cell.2015.10.068. Epub 2015 Nov 19.

Authors

Chao Wang¹, Nir Yosef², Jellert Gaublomme³, Chuan Wu¹, Youjin Lee¹, Clary B Clish⁴, Jim Kaminski⁵, Sheng Xiao¹, Gerd Meyer Zu Horste¹, Mathias Pawlak¹, Yasuhiro Kishi⁶, Nicole Joller¹, Katarzyna Karwacz¹, Chen Zhu¹, Maria Ordovas-Montanes¹, Asaf Madi⁷, Ivo Wortman⁴, Toru Miyazaki⁸, Raymond A Sobel⁹, Hongkun Park³, Aviv Regev¹⁰, Vijay K Kuchroo¹¹

Affiliations

¹ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
² Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology and Department of Physics, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
⁴ Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
⁵ Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁶ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho 1000, Yokohama, 225-0002, Japan.
⁷ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
⁸ Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
⁹ Palo Alto Veteran's Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Howard Hughes Medical Institute and David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 20140, USA. Electronic address: [email protected].
¹¹ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA. Electronic address: [email protected].

Abstract

Th17 cells play a critical role in host defense against extracellular pathogens and tissue homeostasis but can induce autoimmunity. The mechanisms implicated in balancing "pathogenic" and "non-pathogenic" Th17 cell states remain largely unknown. We used single-cell RNA-seq to identify CD5L/AIM as a regulator expressed in non-pathogenic, but not in pathogenic Th17 cells. Although CD5L does not affect Th17 differentiation, it is a functional switch that regulates the pathogenicity of Th17 cells. Loss of CD5L converts non-pathogenic Th17 cells into pathogenic cells that induce autoimmunity. CD5L mediates this effect by modulating the intracellular lipidome, altering fatty acid composition and restricting cholesterol biosynthesis and, thus, ligand availability for Rorγt, the master transcription factor of Th17 cells. Our study identifies CD5L as a critical regulator of the Th17 cell functional state and highlights the importance of lipid metabolism in balancing immune protection and disease induced by T cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / metabolism*
Cell Differentiation
Central Nervous System / pathology
Cholesterol / biosynthesis
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / pathology*
Fatty Acids, Unsaturated / metabolism
Humans
Lipid Metabolism*
Lymph Nodes / pathology
Mice
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
Receptor Tyrosine Kinase-like Orphan Receptors / metabolism
Receptors, Immunologic / metabolism*
Receptors, Scavenger
Single-Cell Analysis
Th17 Cells / immunology
Th17 Cells / pathology*

Substances

Apoptosis Regulatory Proteins
Cd5l protein, mouse
Fatty Acids, Unsaturated
Nuclear Receptor Subfamily 1, Group F, Member 3
Receptors, Immunologic
Receptors, Scavenger
Rorc protein, mouse
Cholesterol
Receptor Tyrosine Kinase-like Orphan Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding