Oleic acid availability impacts thymocyte preprogramming and subsequent peripheral Treg cell differentiation

  • Nat Immunol. 2023 Dec 7. doi: 10.1038/s41590-023-01672-1.
Liangyu Lin  #  1 ,  Mingyuan Hu  #  1 ,  Qing Li  1 ,  Liming Du  1 ,  Li Lin  2 ,  Yueqing Xue  1 ,  Fanjun Zheng  1 ,  Fei Wang  1 ,  Keli Liu  2 ,  Yu Wang  1 ,  Jiayin Ye  1 ,  Xu Jiang  1 ,  Xuefeng Wang  1 ,  Jiaqi Wang  1 ,  Jingjie Zhai  1 ,  Benming Liu  1 ,  Hongzhen Xie  1 ,  Yanqin You  3 ,  Jinyong Wang  4 ,  Xiangyin Kong  1 ,  Dechun Feng  1 ,  Douglas R Green  5 ,  Yufang Shi  6  7 ,  Ying Wang  8
Affiliations
  • 1. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 3. Department of Obstetrics and Gynecology, First Medical Center of Chinese PLA General Hospital, Beijing, China.
  • 4. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
  • 5. Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 6. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 7. The Third Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, China. [email protected].
  • 8. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 38062135 DOI: 10.1038/s41590-023-01672-1
Abstract

The nature of activation signals is essential in determining T cell subset differentiation; however, the features that determine T cell subset preference acquired during intrathymic development remain elusive. Here we show that naive CD4+ T cells generated in the mouse thymic microenvironment lacking Scd1, encoding the enzyme catalyzing oleic acid (OA) production, exhibit enhanced regulatory T (Treg) cell differentiation and attenuated development of experimental autoimmune encephalomyelitis. Scd1 deletion in K14+ thymic epithelia recapitulated the enhanced Treg cell differentiation phenotype of Scd1-deficient mice. The dearth of OA permitted DOT1L to increase H3K79me2 levels at the Atp2a2 locus of thymocytes at the DN2-DN3 transition stage. Such epigenetic modification persisted in naive CD4+ T cells and facilitated Atp2a2 expression. Upon T cell receptor activation, ATP2A2 enhanced the activity of the calcium-NFAT1-Foxp3 axis to promote naive CD4+ T cells to differentiate into Treg cells. Therefore, OA availability is critical for preprogramming thymocytes with Treg cell differentiation propensities in the periphery.

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