title: CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity.
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.
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Nir
authors.initials: N
authors.lastname: Yosef
authors.affiliation: 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.
authors.forename: Jellert
authors.initials: J
authors.lastname: Gaublomme
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Kaminski
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Gerd
authors.initials: G
authors.lastname: Meyer Zu Horste
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Pawlak
authors.affiliation: 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.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kishi
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Joller
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Karwacz
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Ordovas-Montanes
authors.affiliation: 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.
authors.forename: Asaf
authors.initials: A
authors.lastname: Madi
authors.affiliation: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Ivo
authors.initials: I
authors.lastname: Wortman
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Palo Alto Veteran's Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.affiliation: 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.
authors.forename: Hongkun
authors.initials: H
authors.lastname: Park
authors.affiliation: 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: aregev@broadinstitute.org.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.affiliation: 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: vkuchroo@evergrande.hms.harvard.edu.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002490:Central Nervous System / Q000473:pathology; D002784:Cholesterol / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D051116:Receptors, Scavenger; D059010:Single-Cell Analysis; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C117272:Cd5l protein, mouse; D005231:Fatty Acids, Unsaturated; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C539901:Rorc protein, mouse; D002784:Cholesterol; D057050:Receptor Tyrosine Kinase-like Orphan Receptors