CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity

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...

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Bibliographic Details
Published in:Cell 2015-12, Vol.163 (6), p.1413-1427
Main Authors: Wang, Chao, Yosef, Nir, Gaublomme, Jellert, Wu, Chuan, Lee, Youjin, Clish, Clary B., Kaminski, Jim, Xiao, Sheng, Zu Horste, Gerd Meyer, Pawlak, Mathias, Kishi, Yasuhiro, Joller, Nicole, Karwacz, Katarzyna, Zhu, Chen, Ordovas-Montanes, Maria, Madi, Asaf, Wortman, Ivo, Miyazaki, Toru, Sobel, Raymond A., Park, Hongkun, Regev, Aviv, Kuchroo, Vijay K.
Format: Article
Language:English
Subjects:
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
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Summary: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. [Display omitted] •CD5L is preferentially expressed in non-pathogenic Th17 cells•CD5L is a major switch of Th17 cell functional states in vivo•CD5L regulates T cell lipidome in correlation with Th17 cell function•CD5L alters T cell function through PUFA/SFA balance and Rorγt ligand availability CD5L operates as a critical switch of Th17 cells functional states, regulating their ability to cause disease through changes in lipid metabolism and function of the master transcription factor Rorγt.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2015.10.068