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      Thymic Epithelial Cells Contribute to Thymopoiesis and T Cell Development

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          Abstract

          The thymus is the primary lymphoid organ responsible for the generation and maturation of T cells. Thymic epithelial cells (TECs) account for the majority of thymic stromal components. They are further divided into cortical and medullary TECs based on their localization within the thymus and are involved in positive and negative selection, respectively. Establishment of self-tolerance in the thymus depends on promiscuous gene expression (pGE) of tissue-restricted antigens (TRAs) by TECs. Such pGE is co-controlled by the autoimmune regulator (Aire) and forebrain embryonic zinc fingerlike protein 2 (Fezf2). Over the past two decades, research has found that TECs contribute greatly to thymopoiesis and T cell development. In turn, signals from T cells regulate the differentiation and maturation of TECs. Several signaling pathways essential for the development and maturation of TECs have been discovered. New technology and animal models have provided important observations on TEC differentiation, development, and thymopoiesis. In this review, we will discuss recent advances in classification, development, and maintenance of TECs and mechanisms that control TEC functions during thymic involution and central tolerance.

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          Most cited references107

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          Projection of an immunological self shadow within the thymus by the aire protein.

          Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.
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            Mechanisms of Wnt signaling in development.

            Wnt genes encode a large family of secreted, cysteine-rich proteins that play key roles as intercellular signaling molecules in development. Genetic studies in Drosophila and Caenorhabditis elegans, ectopic gene expression in Xenopus, and gene knockouts in the mouse have demonstrated the involvement of Wnts in processes as diverse as segmentation, CNS patterning, and control of asymmetric cell divisions. The transduction of Wnt signals between cells proceeds in a complex series of events including post-translational modification and secretion of Wnts, binding to transmembrane receptors, activation of cytoplasmic effectors, and, finally, transcriptional regulation of target genes. Over the past two years our understanding of Wnt signaling has been substantially improved by the identification of Frizzled proteins as cell surface receptors for Wnts and by the finding that beta-catenin, a component downstream of the receptor, can translocate to the nucleus and function as a transcriptional activator. Here we review recent data that have started to unravel the mechanisms of Wnt signaling.
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              p63 Is essential for the proliferative potential of stem cells in stratified epithelia.

              The distinguishing feature of adult stem cells is their extraordinary capacity to divide prior to the onset of senescence. While stratified epithelia such as skin, prostate, and breast are highly regenerative and account disproportionately for human cancers, genes essential for the proliferative capacity of their stem cells remain unknown. Here we analyze p63, a gene whose deletion in mice results in the catastrophic loss of all stratified epithelia. We demonstrate that p63 is strongly expressed in epithelial cells with high clonogenic and proliferative capacity and that stem cells lacking p63 undergo a premature proliferative rundown. Additionally, we show that p63 is dispensable for both the commitment and differentiation of these stem cells during tissue morphogenesis. Together, these data identify p63 as a key, lineage-specific determinant of the proliferative capacity in stem cells of stratified epithelia.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                31 January 2020
                2019
                : 10
                : 3099
                Affiliations
                [1] 1Laboratory Medicine Center, Nanfang Hospital, Southern Medical University , Guangzhou, China
                [2] 2State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing, China
                [3] 3Department of General Surgery, Taihe Branch of Nanfang Hospital, Southern Medical University , Guangzhou, China
                [4] 4Division of Allergy and Immunology, Department of Pediatrics, Duke University Medical Center , Durham, NC, United States
                [5] 5Department of Urological Organ Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University , Changsha, China
                Author notes

                Edited by: Avinash Bhandoola, National Institutes of Health (NIH), United States

                Reviewed by: Laijun Lai, University of Connecticut, United States; Katsuto Hozumi, School of Medicine, Tokai University, Japan

                *Correspondence: Yong Zhao zhaoy@ 123456ioz.ac.cn

                This article was submitted to T Cell Biology, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2019.03099
                7005006
                32082299
                18dca89a-73ef-4a57-a356-51b4323cebfe
                Copyright © 2020 Wang, Pan, Zheng, Zhong, Tan, Liang, He, Feng, Zhao and Qiu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 October 2019
                : 18 December 2019
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 115, Pages: 10, Words: 8382
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 31800754
                Award ID: 8180051963
                Categories
                Immunology
                Review

                Immunology
                thymic epithelial cells (tecs),medullary thymic epithelial cells (mtecs),thymopoiesis,tissue-restricted antigens (tras),tolerance

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