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

CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity.

Author information

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: aregev@broadinstitute.org.
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: vkuchroo@evergrande.hms.harvard.edu.

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.

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PMID:
26607793
PMCID:
PMC4671820
DOI:
10.1016/j.cell.2015.10.068
[Indexed for MEDLINE]
Free PMC Article

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