CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity.
CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity.
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DOI：
10.1016/j.cell.2015.10.068
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发表时间：
2015-12-03
期刊：
影响因子：
64.5
通讯作者：
Kuchroo VK
中科院分区：
文献类型：
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作者：
Wang C;Yosef N;Gaublomme J;Wu C;Lee Y;Clish CB;Kaminski J;Xiao S;Meyer Zu Horste G;Pawlak M;Kishi Y;Joller N;Karwacz K;Zhu C;Ordovas-Montanes M;Madi A;Wortman I;Miyazaki T;Sobel RA;Park H;Regev A;Kuchroo VK
Th17 细胞在宿主防御细胞外病原体和组织稳态方面发挥着关键作用，但可以诱导自身免疫。平衡“致病性”和“非致病性”Th17 细胞状态所涉及的机制仍然很大程度上未知。我们使用单细胞 RNA-seq 来鉴定 CD5L/AIM 作为在“非致病性”而非“致病性”Th17 细胞中表达的调节因子。尽管CD5L不影响Th17分化，但它是调节Th17细胞致病性的功能开关。 CD5L 的缺失会将“非致病性”Th17 细胞转化为诱导自身免疫的“致病性”细胞。 CD5L 通过调节细胞内脂质组、改变脂肪酸组成和限制胆固醇生物合成来介导这种效应，从而限制 Th17 细胞的主转录因子 Rorγt 的配体可用性。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 细胞诱导的疾病中的重要性。
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.