Metabolic control of TFH cells and humoral immunity by phosphatidylethanolamine

Guotong Fu, Clifford S. Guy, Nicole M. Chapman, Gustavo Palacios, Jun Wei, Peipei Zhou, Lingyun Long, Yong-Dong Wang, Chenxi Qian, Yogesh Dhungana, Hongling Huang, Anil Kc, Hao Shi, Sherri Rankin, Scott A. Brown, Amanda Johnson, Randall Wakefield, Camenzind G. Robinson, Xueyan Liu, Anthony Sheyn, Jiyang Yu, Suzanne Jackowski and Hongbo Chi ()
Additional contact information
Guotong Fu: St. Jude Children’s Research Hospital
Clifford S. Guy: St. Jude Children’s Research Hospital
Nicole M. Chapman: St. Jude Children’s Research Hospital
Gustavo Palacios: St. Jude Children’s Research Hospital
Jun Wei: St. Jude Children’s Research Hospital
Peipei Zhou: St. Jude Children’s Research Hospital
Lingyun Long: St. Jude Children’s Research Hospital
Yong-Dong Wang: St. Jude Children’s Research Hospital
Chenxi Qian: St. Jude Children’s Research Hospital
Yogesh Dhungana: St. Jude Children’s Research Hospital
Hongling Huang: St. Jude Children’s Research Hospital
Anil Kc: St. Jude Children’s Research Hospital
Hao Shi: St. Jude Children’s Research Hospital
Sherri Rankin: St. Jude Children’s Research Hospital
Scott A. Brown: St. Jude Children’s Research Hospital
Amanda Johnson: St. Jude Children’s Research Hospital
Randall Wakefield: St. Jude Children’s Research Hospital
Camenzind G. Robinson: St. Jude Children’s Research Hospital
Xueyan Liu: University of New Orleans
Anthony Sheyn: St. Jude Children’s Research Hospital
Jiyang Yu: St. Jude Children’s Research Hospital
Suzanne Jackowski: St. Jude Children’s Research Hospital
Hongbo Chi: St. Jude Children’s Research Hospital

Nature, 2021, vol. 595, issue 7869, 724-729

Abstract: Abstract T follicular helper (TFH) cells are crucial for B cell-mediated humoral immunity1. Although transcription factors such as BCL6 drive the differentiation of TFH cells2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce TFH cell programming. Here we show that the cytidine diphosphate (CDP)–ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of TFH cells and humoral immunity. Using in vivo CRISPR–Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI—enzymes in the CDP–ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)—as selective post-transcriptional regulators of TFH cell differentiation that act by promoting the surface expression and functional effects of CXCR5. TFH cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP–ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP–choline pathway), in activated T cells impairs the differentiation of TFH cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for TFH cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs.

Date: 2021
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DOI: 10.1038/s41586-021-03692-z

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