title: Trx1/TrxR1 system regulates post-selected DP thymocytes survival by modulating ASK1-JNK/p38 MAPK activities.
abstract: A key process in the development of T lymphocyte in the thymus is T-cell receptor (TCR) selection. It is controlled by complex signaling pathways that contain redox-sensitive molecules. However, the redox status early after TCR selection and how redox regulators promote the survival of post-selected DP thymocytes has not been directly addressed. The present study demonstrated that the transition from pre- to post-selected double-positive (DP) stages was accompanied with an increase of reactive oxygen species (ROS) and a transient surge in the expression of a variety of redox regulators. Among them, the thioredoxin (Trx)1/thioredoxin reductase (TrxR)1 system was found to be critically involved in the regulation of cell survival of DP thymocytes, especially that of post-selected CD69(+) subset, as its inhibition caused a specific reduction of these cells both in vitro and in vivo, most likely owing to increased apoptosis. Suppression of the glutathione-dependent redox system, on the other hand, showed no obvious impact. Biochemically, treatment of DP thymcoytes with TrxR1 inhibitor alone or in conjunction with anti-CD3 resulted in enhanced phosphorylation of redox-sensitive ASK-1, JNK and p38 MAPK, and upregulated expression of Bim. Taken together, the data presented here suggest that the timely upregulation of Trx1/TrxR1 and the active control of intracellular redox status is critical for the survival of thymocytes during and short after positive selection.
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Jin
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Shusong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Teng
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Xu
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Abudureyimujiang
authors.initials: A
authors.lastname: Aili
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Xiuyuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Pang
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ge
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D015870:Gene Expression; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010084:Oxidation-Reduction; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D054481:Thioredoxin Reductase 1 / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D046509:Tissue Culture Techniques; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; D013879:Thioredoxins; D054481:Thioredoxin Reductase 1; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5