Wang Chao, Yosef Nir, Gaublomme Jellert, Wu Chuan, Lee Youjin, Clish Clary B, Kaminski Jim, Xiao Sheng, Meyer Zu Horste Gerd, 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
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; 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.
Cell. 2015 Dec 3;163(6):1413-27. doi: 10.1016/j.cell.2015.10.068. Epub 2015 Nov 19.
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.
辅助性T细胞17（Th17细胞）在宿主抵御细胞外病原体和维持组织内稳态中发挥关键作用，但也可诱发自身免疫。目前，平衡“致病性”和“非致病性”Th17细胞状态的机制仍不清楚。我们利用单细胞RNA测序确定CD5L/AIM是一种在非致病性Th17细胞而非致病性Th17细胞中表达的调节因子。虽然CD5L不影响Th17细胞分化，但它是调节Th17细胞致病性的功能开关。CD5L缺失会将非致病性Th17细胞转变为诱发自身免疫的致病性细胞。CD5L通过调节细胞内脂质组、改变脂肪酸组成并限制胆固醇生物合成，进而限制Th17细胞主转录因子Rorγt的配体可用性，来介导这一效应。我们的研究确定CD5L是Th17细胞功能状态的关键调节因子，并强调了脂质代谢在平衡免疫保护和T细胞诱导疾病中的重要性。
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