The Teams of Profs. Ying Wang and Yufang Shi reveal a novel mechanism of thymic oleic acid in regulating peripheral Treg differentiation
Source：Ying Wang
2023-12-26
The appearance of thymus in jawed vertebrates is a critical evolutionary event for the establishment of adaptive immunity. As the organ for generating T cells, thymus is well conserved structurally and functionally. Upon arriving in the thymus, common lymphoid progenitors from bone marrow are supported by multiple signals from thymic stromal cells to undergo T cell development program, sequentially through the CD4-CD8- double-negative (DN) stage, CD4+CD8+ double-positive (DP) stage, and CD4+ or CD8+ single-positive (SP) stage. Upon the expression of the T cell antigen receptors, the developing T cells are subjected to negative and positive selections to remove non-functional and potential autoreactive thymocytes. The remaining SP cells are permitted to depart the thymus and enter the circulation and peripheral lymphoid organs. These newly developed T cells in the periphery are considered as naïve T cells. In response to antigen stimuli and various kinds of cytokines, naïve T cells activate and differentiate into distinct subsets, closely relating to metabolic and epigenetic regulation. However, it is not known whether developing T cells received various signals from the thymic environment could cause long lasting effect on naïve T cells and determine their reactivity to activation through metabolic and epigenetic regulation.
On December 7th, 2023, a research article entitled "Oleic Acid Availability Impacts Thymocyte Preprogramming and Subsequent Peripheral Treg Cell Differentiation" was published online in Nature Immunology. This study was led by Professor Ying Wang from the Shanghai Institute of Nutrition and Health, CAS and Professor Yufang Shi from the Soochow University Institutes for Translational Medicine and found that oleic acid shortage in the thymus affects CD4-CD8- double-negative (DN) thymocytes and leaves permanent epigenetic imprint on naive CD4+ T cells to allow their increased tendency to differentiate in regulatory T cells (Tregs) in periphery. This discovery unveils a novel cellular and molecular mechanism underlining the regulation of T cell subset differentiation.
Stearoyl-Coenzyme A desaturase-1 (SCD1) is a rate-limiting enzyme that converts saturated fatty acids (16:0, 18:0) into monounsaturated fatty acids, including oleic acid (18:1;9) and palmitoleic acid (16:1;7). In this study, researchers observed that SCD1-deficient mice show an increase in the number of regulatory T cells (Tregs) in the peripheral blood, secondary lymphoid organs, and major organs. Such high levels of Tregs endowed SCD1-/- mice with the ability to resist experimental autoimmune encephalomyelitis (EAE). These naïve T cells from SCD1-/- mice showed intrinsic properties to differentiate into Tregs, however, this intrinsic properties was not relate to the direct influence of SCD1 on T cells. Using bone marrow chimera, thymus transplantations, and thymocyte adaptive transfers, the researchers found that lack of SCD1 in thymus stroma is responsible for the preference of naïve T cell to differentiate into Tregs and such Treg preference was acquired at the transition stage of DN2 to DN3.
When SCD1 was absent, the thymic oleic acid levels were dramatically reduced. Supplementation of oleic acid can reverse the inclination of naïve T cells of SCD1-/- mice toward Treg differentiation in both in vitro and in vivo systems. Interestingly, the thymic oleic acid levels are governed by the activities of SCD1 in Keratin14+ (K14) thymic epithelial cells. Deletion of SCD1 in K14+ epithelia recapitulated the enhanced Treg differentiation tendency and EAE resistance of SCD1-/- mice. The dearth of oleic acid permitted Dot1L to increase the H3K79me2 level at the Atp2a2 locus of thymocytes during the DN2-DN3 transition stage. Such epigenetic modification persisted until naïve CD4+ T cells and facilitated the expression of Atp2a2, an ER Ca2+ channel. Upon TCR activation, Atp2a2 enhanced the activity of the calcium-NFAT1-Foxp3 axis to promote naïve CD4+ T cells to differentiate into Tregs. Therefore, the oleic acid availability in the thymic stromal microenvironment preprograms thymocytes and subsequent peripheral T cell subset differentiation.
This study highlights that the thymocytes maturation process in the thymus is a critical stage to be imprinted for their subset differentiation and function in periphery. This study provide critical information for designing innovative strategies to efficiently induce Tregs to improve organ transplantation and autoimmune diseases.
Dr. Liangyu Lin, a postdoctoral fellow, and Mingyuan Hu, a doctoral student at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, are the co-first authors of this publication. This work received collaborative support from Prof. Xiangyin Kong of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Prof. Jinyong Wang of the CAS Key Laboratory of Stem Cell and Regenerative Medicine, and Prof. Li Lin of ShanghaiTech University. This project was funded by the National Key Research and Development Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, the China Birth Defects Rescue Foundation, as well as the research technology platform and animal platform of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences.
Link: https://www.nature.com/articles/s41590-023-01672-1
On December 7th, 2023, a research article entitled "Oleic Acid Availability Impacts Thymocyte Preprogramming and Subsequent Peripheral Treg Cell Differentiation" was published online in Nature Immunology. This study was led by Professor Ying Wang from the Shanghai Institute of Nutrition and Health, CAS and Professor Yufang Shi from the Soochow University Institutes for Translational Medicine and found that oleic acid shortage in the thymus affects CD4-CD8- double-negative (DN) thymocytes and leaves permanent epigenetic imprint on naive CD4+ T cells to allow their increased tendency to differentiate in regulatory T cells (Tregs) in periphery. This discovery unveils a novel cellular and molecular mechanism underlining the regulation of T cell subset differentiation.
Stearoyl-Coenzyme A desaturase-1 (SCD1) is a rate-limiting enzyme that converts saturated fatty acids (16:0, 18:0) into monounsaturated fatty acids, including oleic acid (18:1;9) and palmitoleic acid (16:1;7). In this study, researchers observed that SCD1-deficient mice show an increase in the number of regulatory T cells (Tregs) in the peripheral blood, secondary lymphoid organs, and major organs. Such high levels of Tregs endowed SCD1-/- mice with the ability to resist experimental autoimmune encephalomyelitis (EAE). These naïve T cells from SCD1-/- mice showed intrinsic properties to differentiate into Tregs, however, this intrinsic properties was not relate to the direct influence of SCD1 on T cells. Using bone marrow chimera, thymus transplantations, and thymocyte adaptive transfers, the researchers found that lack of SCD1 in thymus stroma is responsible for the preference of naïve T cell to differentiate into Tregs and such Treg preference was acquired at the transition stage of DN2 to DN3.
When SCD1 was absent, the thymic oleic acid levels were dramatically reduced. Supplementation of oleic acid can reverse the inclination of naïve T cells of SCD1-/- mice toward Treg differentiation in both in vitro and in vivo systems. Interestingly, the thymic oleic acid levels are governed by the activities of SCD1 in Keratin14+ (K14) thymic epithelial cells. Deletion of SCD1 in K14+ epithelia recapitulated the enhanced Treg differentiation tendency and EAE resistance of SCD1-/- mice. The dearth of oleic acid permitted Dot1L to increase the H3K79me2 level at the Atp2a2 locus of thymocytes during the DN2-DN3 transition stage. Such epigenetic modification persisted until naïve CD4+ T cells and facilitated the expression of Atp2a2, an ER Ca2+ channel. Upon TCR activation, Atp2a2 enhanced the activity of the calcium-NFAT1-Foxp3 axis to promote naïve CD4+ T cells to differentiate into Tregs. Therefore, the oleic acid availability in the thymic stromal microenvironment preprograms thymocytes and subsequent peripheral T cell subset differentiation.
This study highlights that the thymocytes maturation process in the thymus is a critical stage to be imprinted for their subset differentiation and function in periphery. This study provide critical information for designing innovative strategies to efficiently induce Tregs to improve organ transplantation and autoimmune diseases.
Dr. Liangyu Lin, a postdoctoral fellow, and Mingyuan Hu, a doctoral student at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, are the co-first authors of this publication. This work received collaborative support from Prof. Xiangyin Kong of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Prof. Jinyong Wang of the CAS Key Laboratory of Stem Cell and Regenerative Medicine, and Prof. Li Lin of ShanghaiTech University. This project was funded by the National Key Research and Development Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, the China Birth Defects Rescue Foundation, as well as the research technology platform and animal platform of the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences.
Link: https://www.nature.com/articles/s41590-023-01672-1
