Neonatal testosterone imprinting affects thymus development and leads to phenotypic rejuvenation and masculinization of the peripheral blood T-cell compartment in adult female rats |
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| Authors: | Gordana Leposavić Milica Perišić Duško Kosec Nevena Arsenović-Ranin Katarina Radojević Zorica Stojić-Vukanić Ivan Pilipović |
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| Affiliation: | 1. Immunology Research Centre “Branislav Jankovi?”, Institute of Virology, Vaccines and Sera “Torlak”, 458 Vojvode Stepe, 11221 Belgrade, Serbia;2. Department of Physiology, Faculty of Pharmacy, 450 Vojvode Stepe, 11221 Belgrade, Serbia;3. Department of Microbiology and Immunology, Faculty of Pharmacy, 450 Vojvode Stepe, 11221 Belgrade, Serbia;1. Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;2. Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy;3. Internal Medicine and Hepatology Unit, Humanitas Research Hospital, Rozzano, Milan, Italy;1. Althea and Tyho-Galileo Research Laboratories, Reprogenetics, 3 Regent Street, Livingston, NJ 07039, USA;2. Center for Human Reproduction, North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030, USA;1. Department of Medical Imaging, The First Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, PR China;2. Departments of Oncology & Pathology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan 430071, PR China;3. Department of General Surgery, Shanxi Dayi Hospital, Taiyuan 030001, PR China;4. Department of Surgery, Heji Hospital Affiliated to Changzhi Medical College, Changzhi 046000, PR China;1. State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China;2. Beijing Key Laboratory of Environmentally Harmful Chemical Analysis, Beijing University of Chemical Technology, Beijing 100029, China;1. National Microbiology Laboratory, Winnipeg, Manitoba, Canada;2. Medical Microbiology, University of Manitoba, Canada;3. Medical Microbiology, University of Nairobi, Nairobi, Kenya |
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| Abstract: | Exposure of female rodents to testosterone in the critical neonatal period produces defeminization/masculinization of the hypothalamo–pituitary–gonadal (HPG) axis, i.e. neonatal androgenization and postpones axis maturation. To address the hypothesis that HPG axis signaling is involved in the programming of thymic maturation/involution and sexual differentiation we studied the impact of neonatal androgenization on thymic cellularity, development of effector and regulatory T cells, and phenotypic characteristics of peripheral blood T lymphocytes in adult rats. A single injection of testosterone on postnatal day 2 postponed thymic maturation/involution as revealed by organ hypercellularity, increased cellularity of the most mature (CD4+CD8? and CD4?CD8+) TCRαβhigh thymocyte and both recent thymic emigrant (RTE) subsets and caused phenotypic defeminization/masculinization of thymic (decreased CD4+CD8?TCRαβhigh/CD4?CD8+TCRαβhigh cell ratio) and peripheral blood T-cell compartments (decreased CD4+RTE/CD8+RTE and CD4+/CD8+ cell ratio). In addition, neonatal androgenization increased the relative and absolute numbers of both CD4+CD25+Foxp3+ and natural killer (NK) regulatory T cells in peripheral blood. These findings, in conjunction with thymocyte overexpression of Thy-1 that is assumed to reduce negative selection affecting self-reactive cell generation, suggest a new relationship between self-reactive and regulatory T cells. In conclusion, our study provides additional evidence for a role of HPG signals (i.e. sex steroids and gonadotropins) in programming the kinetics of thymic maturation/involution and in establishing immunological sexual dimorphism. |
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