The Experts below are selected from a list of 276 Experts worldwide ranked by ideXlab platform
Ellen A. Robey - One of the best experts on this subject based on the ideXlab platform.
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Central CD4^+ T cell tolerance: deletion versus regulatory T cell differentiation
Nature Reviews Immunology, 2019Co-Authors: Ludger Klein, Ellen A. Robey, Chyi-song HsiehAbstract:Self-antigen recognition in the thymus can result in both clonal deletion of developing Thymocytes and their diversion into the regulatory T cell lineage. How do Thymocyte-intrinsic and Thymocyte-extrinsic determinants influence this cell fate choice? The diversion of MHC class II-restricted Thymocytes into the regulatory T (T_reg) cell lineage is driven by intrathymic encounter of agonist self-antigens in a similar manner to the clonal deletion of Thymocytes. Somewhat paradoxically, it thus seems that the expression of an autoreactive T cell receptor is a shared characteristic of T cells that are subject to clonal deletion and T cells that are diverted into the T_reg cell lineage. Here, we discuss how Thymocyte-intrinsic and Thymocyte-extrinsic determinants may specify the choice between these two fundamentally different T cell fates.
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Stable Interactions and Sustained TCR Signaling Characterize Thymocyte–Thymocyte Interactions that Support Negative Selection
Journal of Immunology, 2014Co-Authors: Heather J. Melichar, Jenny O. Ross, Kayleigh T. Taylor, Ellen A. RobeyAbstract:Negative selection is one of the primary mechanisms that render T cells tolerant to self. Thymic dendritic cells play an important role in negative selection, in line with their ability to induce migratory arrest and sustained TCR signals. Thymocytes themselves display self-peptide/MHC class I complexes, and although there is evidence that they can support clonal deletion, it is not clear whether they do so directly via stable cell–cell contacts and sustained TCR signals. In this study, we show that murine Thymocytes can support surprisingly efficient negative selection of Ag-specific Thymocytes. Furthermore, we observe that agonist-dependent Thymocyte–Thymocyte interactions occurred as stable, motile conjugates led by the peptide-presenting Thymocyte and in which the trailing peptide-specific Thymocyte exhibited persistent elevations in intracellular calcium concentration. These data confirm that self-Ag presentation by Thymocytes is an additional mechanism to ensure T cell tolerance and further strengthen the correlation between stable cellular contacts, sustained TCR signals, and efficient negative selection.
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Tracking migration during human T cell development
Cellular and Molecular Life Sciences, 2014Co-Authors: Joanna Halkias, Heather J. Melichar, Kayleigh T. Taylor, Ellen A. RobeyAbstract:Specialized microenvironments within the thymus are comprised of unique cell types with distinct roles in directing the development of a diverse, functional, and self-tolerant T cell repertoire. As they differentiate, Thymocytes transit through a number of developmental intermediates that are associated with unique localization and migration patterns. For example, during one particular developmental transition, immature Thymocytes more than double in speed as they become mature T cells that are among the fastest cells in the body. This transition is associated with dramatic changes in the expression of chemokine receptors and their antagonists, cell adhesion molecules, and cytoskeletal components to direct the maturing Thymocyte population from the cortex to medulla. Here we discuss the dynamic changes in behavior that occur throughout Thymocyte development, and provide an overview of the cell-intrinsic and extrinsic mechanisms that regulate human Thymocyte migration.
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opposing chemokine gradients control human Thymocyte migration in situ
Journal of Clinical Investigation, 2013Co-Authors: Joanna Halkias, Heather J. Melichar, Jenny O. Ross, Kayleigh T. Taylor, Samantha B Cooper, Astar Winoto, Ellen A. RobeyAbstract:: The ordered migration of Thymocytes from the cortex to the medulla is critical for the appropriate selection of the mature T cell repertoire. Most studies of Thymocyte migration rely on mouse models, but we know relatively little about how human Thymocytes find their appropriate anatomical niches within the thymus. Moreover, the signals that retain CD4+CD8+ double-positive (DP) Thymocytes in the cortex and prevent them from entering the medulla prior to positive selection have not been identified in mice or humans. Here, we examined the intrathymic migration of human Thymocytes in both mouse and human thymic stroma and found that human Thymocyte subsets localized appropriately to the cortex on mouse thymic stroma and that MHC-dependent interactions between human Thymocytes and mouse stroma could maintain the activation and motility of DP cells. We also showed that CXCR4 was required to retain human DP Thymocytes in the cortex, whereas CCR7 promoted migration of mature human Thymocytes to the medulla. Thus, 2 opposing chemokine gradients control the migration of Thymocytes from the cortex to the medulla. These findings point to significant interspecies conservation in Thymocyte-stroma interactions and provide the first evidence that chemokines not only attract mature Thymocytes to the medulla, but also play an active role in retaining DP Thymocytes in the cortex prior to positive selection.
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Thymocyte motility : mutants, movies and migration patterns
Current Opinion in Immunology, 2006Co-Authors: Tatyana Chtanova, Ena Ladi, Ellen A. RobeyAbstract:Developing T cells are highly motile and undergo long-range migrations in the thymus as part of their developmental program. In the past two years, significant advances have been made in understanding the nature of the signals that control the entry of Thymocyte progenitors into the thymus and the exit of mature Thymocytes from the thymus. Progress has also been made in identifying the chemokine signals that control intrathymic migration patterns. In addition, the recent application of two-photon laser scanning microscopy has made it possible to make real-time observations of Thymocytes within the three-dimensional environment of the thymus, and has shed new light on the relationship between positive selection and Thymocyte migration.
Jonathan D. Ashwell - One of the best experts on this subject based on the ideXlab platform.
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glucocorticoids oppose Thymocyte negative selection by inhibiting helios and nur77
Journal of Immunology, 2019Co-Authors: Paul R Mittelstadt, Matthew D Taves, Jonathan D. AshwellAbstract:: Glucocorticoid (GC) signaling in Thymocytes shapes the TCR repertoire by antagonizing Thymocyte negative selection. The transcription factors Nur77 and Helios, which are upregulated in TCR-signaled Thymocytes, have been implicated in negative selection. In this study, we found that GCs inhibited Helios and, to a lesser extent, Nur77 upregulation in TCR-stimulated mouse Thymocytes. Inhibition was increased by GC preincubation, and reductions in mRNA were prevented by a protein synthesis inhibitor, suggesting that GCs suppress indirectly via an intermediary factor. Upregulation of Helios in TCR-stimulated Thymocytes was unaffected by deletion of Nur77, indicating Nur77 and Helios are regulated independently. Whereas CD4+ Thymocytes are positively selected in wild-type AND TCR-transgenic B6 mice, loss of GC receptor expression resulted in increased negative selection. Correspondingly, Helios and Nur77 levels were elevated in TCRhiCD4+CD8+ (TCR-signaled) Thymocytes. Notably, deletion of Helios fully reversed this negative selection, whereas deletion of Nur77 had no effect on CD4+CD8+ cell numbers but reversed the loss of mature CD4+ Thymocytes. Thus, Nur77 and Helios are GC targets that play nonredundant roles in setting the signaling threshold for Thymocyte negative selection.
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Thymocyte Apoptosis
Journal of Clinical Immunology, 1999Co-Authors: Yili Yang, Jonathan D. AshwellAbstract:Apoptosis is the fate of most Thymocytes. Many molecules participate in the decision of whether a Thymocyte is to live or to die, including cell surface receptors, such as the T cell receptor for antigen, Notch-1, and costimulatory receptors, ligand-regulated nuclear transcription factors such as the glucocorticoid receptor, signaling, and effector proteases, and direct regulators of the apoptotic machinery such IAPs. In this review we discuss recent data concerning these molecules and pathways and their implication for understanding the mechanisms underlying Thymocyte death, survival, and the generation of immunocompetent T cells.
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Thymus-derived glucocorticoids set the thresholds for Thymocyte selection by inhibiting TCR-mediated Thymocyte activation.
Journal of Immunology, 1999Co-Authors: Melanie S. Vacchio, Jonathan D. AshwellAbstract:Selection processes in the thymus eliminate nonfunctional or harmful T cells and allow the survival of those cells with the potential to recognize Ag in association with self-MHC-encoded molecules (Ag/MHC). We have previously demonstrated that thymus-derived glucocorticoids antagonize TCR-mediated deletion, suggesting a role for endogenous thymic glucocorticoids in promoting survival of Thymocytes following TCR engagement. Consistent with this hypothesis, we now show that inhibition of thymus glucocorticoid biosynthesis causes an increase in Thymocyte apoptosis and a decrease in recovery that are directly proportional to the number of MHC-encoded molecules present and, therefore, the number of ligands available for TCR recognition. Expression of CD5 on CD4+CD8+ Thymocytes, an indicator of TCR-mediated activation, increased in a TCR- and MHC-dependent manner when corticosteroid production or responsiveness was decreased. These results indicate that thymus-derived glucocorticoids determine where the window of Thymocyte selection occurs in the TCR avidity spectrum by dampening the biological consequences of TCR occupancy and reveal that glucocorticoids mask the high percentage of self-Ag/MHC-reactive Thymocytes that exist in the preselection repertoire.
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A targeted glucocorticoid receptor antisense transgene increases Thymocyte apoptosis and alters Thymocyte development.
Immunity, 1995Co-Authors: Leslie B. King, Melanie S. Vacchio, Katherine Dixon, Rosemarie Hunziker, David H. Margulies, Jonathan D. AshwellAbstract:Abstract The exquisite sensitivity of Thymocytes to steroid-induced apoptosis, the steroidogenic potential of thymic epithelial cells, and the ability of steroid synthesis inhibitors to enhance antigen-specific deletion of Thymocytes in fetal thymic organ cultures suggest a role for glucocorticoids in Thymocyte development. To address this further, transgenic mice that express anti-sense transcripts to the glucocorticoid receptor (GR) specifically in immature Thymocytes were generated. The consequent hyporesponsiveness of Thymocytes to glucocorticoids was accompanied by a reduction in thymic size, primarily owing to a decrease in the number of CD4 + CD8 + cells. While an enhanced susceptibility to T cell receptor (TCR)-mediated apoptosis appeared to be partially responsible for this reduction, Thymocyte loss could also be detected before Thymocytes progressed to the CD4 + CD8 + TCRαβ-expressing stage. These results suggest that glucocorticoids are necessary for survival and maturation of Thymocytes, and are consistent with a role for steroids in both the transition from CD4 − CD8 − to CD4 + CD8 + cells and the survival of CD4 + CD8 + cells stimulated via the TCR.
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steroid production in the thymus implications for Thymocyte selection
Journal of Experimental Medicine, 1994Co-Authors: Melanie S. Vacchio, Vassilios Papadopoulos, Jonathan D. AshwellAbstract:The mouse thymus was assessed for its ability to produce steroids. Cultured thymic non-T cells produced soluble pregnenolone and deoxycorticosterone, and immunohistochemistry demonstrated steroidogenic enzymes in radioresistant thymic epithelial cells but not in Thymocytes. Inhibition of thymic corticosterone production or blockade of the glucocorticoid receptor with RU-486 resulted in enhanced TCR-mediated, antigen-specific deletion of immature Thymocytes. These data indicate that locally produced glucocorticoids, because of their antagonism of TCR-mediated signaling for death, may be a key element of antigen-specific Thymocyte selection.
Joanna Halkias - One of the best experts on this subject based on the ideXlab platform.
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Tracking migration during human T cell development
Cellular and Molecular Life Sciences, 2014Co-Authors: Joanna Halkias, Heather J. Melichar, Kayleigh T. Taylor, Ellen A. RobeyAbstract:Specialized microenvironments within the thymus are comprised of unique cell types with distinct roles in directing the development of a diverse, functional, and self-tolerant T cell repertoire. As they differentiate, Thymocytes transit through a number of developmental intermediates that are associated with unique localization and migration patterns. For example, during one particular developmental transition, immature Thymocytes more than double in speed as they become mature T cells that are among the fastest cells in the body. This transition is associated with dramatic changes in the expression of chemokine receptors and their antagonists, cell adhesion molecules, and cytoskeletal components to direct the maturing Thymocyte population from the cortex to medulla. Here we discuss the dynamic changes in behavior that occur throughout Thymocyte development, and provide an overview of the cell-intrinsic and extrinsic mechanisms that regulate human Thymocyte migration.
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opposing chemokine gradients control human Thymocyte migration in situ
Journal of Clinical Investigation, 2013Co-Authors: Joanna Halkias, Heather J. Melichar, Jenny O. Ross, Kayleigh T. Taylor, Samantha B Cooper, Astar Winoto, Ellen A. RobeyAbstract:: The ordered migration of Thymocytes from the cortex to the medulla is critical for the appropriate selection of the mature T cell repertoire. Most studies of Thymocyte migration rely on mouse models, but we know relatively little about how human Thymocytes find their appropriate anatomical niches within the thymus. Moreover, the signals that retain CD4+CD8+ double-positive (DP) Thymocytes in the cortex and prevent them from entering the medulla prior to positive selection have not been identified in mice or humans. Here, we examined the intrathymic migration of human Thymocytes in both mouse and human thymic stroma and found that human Thymocyte subsets localized appropriately to the cortex on mouse thymic stroma and that MHC-dependent interactions between human Thymocytes and mouse stroma could maintain the activation and motility of DP cells. We also showed that CXCR4 was required to retain human DP Thymocytes in the cortex, whereas CCR7 promoted migration of mature human Thymocytes to the medulla. Thus, 2 opposing chemokine gradients control the migration of Thymocytes from the cortex to the medulla. These findings point to significant interspecies conservation in Thymocyte-stroma interactions and provide the first evidence that chemokines not only attract mature Thymocytes to the medulla, but also play an active role in retaining DP Thymocytes in the cortex prior to positive selection.
Wilson Savino - One of the best experts on this subject based on the ideXlab platform.
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Triiodothyronine modulates Thymocyte migration.
Scandinavian Journal of Immunology, 2007Co-Authors: Marilza Moura Ribeiro-carvalho, K. R. F. Lima-quaresma, T. Mouço, V. F. Carvalho, Valeria De Mello-coelho, Wilson SavinoAbstract:Triiodothyronine (T3) exerts several effects on thymus physiology. In this sense, T3 is known to stimulate thymic microenvironmental cells to enhance the production of extracellular matrix (ECM) moieties, which are relevant in Thymocyte migration. Here, we further investigated the in vivo influence of T3 on ECM production, as well as on ECM-related T-cell migration events. For this, BALB/c mice were subjected to two protocols of T3 treatment: long-term (30 days) i.p. daily T3 injections or short-term (16 h) after a single T3 intrathymic injection. These two treatments did promote an enhancement in the expression of fibronectin and laminin, in both cortex and medullary regions of the thymic lobules. As revealed by the long-term treatment, the expression of ECM protein receptors, including VLA-4, VLA-5 and VLA-6, was also increased in Thymocyte subsets issued from T3-treated mice. We further used thymic nurse cells (TNC) as an in vitro system to study the ECM-related migration of immature Thymocytes in the context of thymic epithelial cells. Even a single intrathymic injection of T3 resulted in an increase in the ex vivo exit of Thymocytes from TNC lymphoepithelial complexes. Accordingly, when we evaluated Thymocyte migration in transwell chambers pre-coated with ECM proteins, we found an increase in the numbers of migrating cells, when Thymocytes were derived from T3-treated mice. Overall, our data show that in vivo intrathymic short-term i.p. long-term T3 treatments are able to modulate Thymocyte migration, probably via ECM-mediated interactions.
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control of human Thymocyte migration by neuropilin 1 semaphorin 3a mediated interactions
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Yves Lepelletier, Salete Smaniotto, Mireille Dardenne, Reda Hadjslimane, Dea Maria Serra Villaverde, Ana Cristina Martins De Almeida Nogueira, Olivier Hermine, Wilson SavinoAbstract:It is largely established that molecules first discovered in the nervous system are also found in the immune system. Neuropilin-1 (NP-1) was initially identified to mediate semaphorin-induced chemorepulsion during brain development and is also involved in peripheral T cell/dendritic cell interactions. Herein, we studied NP-1 during T cell development in the human thymus. NP-1 is expressed in both cortex and medulla of thymic lobules, being found in distinct CD4/CD8-defined Thymocyte subsets. NP-1 is also found in thymic epithelial cells (TEC) in situ and in vitro, and is recruited at the site of TEC–Thymocyte contact. Moreover, NP-1 was rapidly up-regulated during Thymocyte stimulation by T cell receptor (TCR) and IL-7 or after adhesion to TEC. Semaphorin-3A (Sema-3A), a natural ligand of NP-1, is also present in human thymus, both in TEC and Thymocytes, being up-regulated in Thymocytes after TCR engagement. Functionally, Sema-3A decreases the adhesion capacity of NP-1+ Thymocytes and induces their migration by a repulsive effect. In conclusion, we show here that NP-1/Sema-3A-mediated interactions participate in the control of human Thymocyte development.
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the thymus gland a target organ for growth hormone
Scandinavian Journal of Immunology, 2002Co-Authors: Wilson Savino, Marie Catherine Postelvinay, Salete Smaniotto, Mireille DardenneAbstract:Increasing evidence has placed hormones and neuropeptides among potent immunomodulators, in both health and disease. Herein, we focus on the effects of growth hormone (GH) upon the thymus. Exogenous GH enhances thymic microenvironmental cell-derived secretory products such as cytokines and thymic hormones. Moreover, GH increases thymic epithelial cell (TEC) proliferation in vitro, and exhibits a synergistic effect with anti-CD3 in stimulating Thymocyte proliferation, which is in keeping with the data showing that transgenic mice overexpressing GH or GH-releasing hormone exhibit overgrowth of the thymus. GH also influences Thymocyte traffic: it increases human T-cell progenitor engraftment into the thymus; augments TEC/Thymocyte adhesion and the traffic of Thymocytes in the lymphoepithelial complexes, the thymic nurse cells; modulates in vivo the homing of recent thymic emigrants, enhancing the numbers of fluroscein isothiocyanate (FITC)+ cells in the lymph nodes and diminishing them in the spleen. In keeping with the effects of GH upon thymic cells is the detection of GH receptors in both TEC and Thymocytes. Additionally, data indicate that insulin-like growth factor (IGF)-1 is involved in several effects of GH in the thymus, including the modulation of thymulin secretion, TEC proliferation as well as Thymocyte/TEC adhesion. This is in keeping with the demonstration of IGF-1 production and expression of IGF-1 by TEC and Thymocytes. Also, it should be envisioned as an intrathymic circuitry, involving not only IGF-1, but also GH itself, as intrathymic GH expression is seen both in TEC and in Thymocytes, and that Thymocyte-derived GH could enhance Thymocyte proliferation. Finally, the possibility that GH improve thymic functions, including Thymocyte proliferation and migration, places this molecule as a potential therapeutic adjuvant in immunodeficiency conditions associated with Thymocyte decrease and loss of peripheral T cells.
Heather J. Melichar - One of the best experts on this subject based on the ideXlab platform.
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Stable Interactions and Sustained TCR Signaling Characterize Thymocyte–Thymocyte Interactions that Support Negative Selection
Journal of Immunology, 2014Co-Authors: Heather J. Melichar, Jenny O. Ross, Kayleigh T. Taylor, Ellen A. RobeyAbstract:Negative selection is one of the primary mechanisms that render T cells tolerant to self. Thymic dendritic cells play an important role in negative selection, in line with their ability to induce migratory arrest and sustained TCR signals. Thymocytes themselves display self-peptide/MHC class I complexes, and although there is evidence that they can support clonal deletion, it is not clear whether they do so directly via stable cell–cell contacts and sustained TCR signals. In this study, we show that murine Thymocytes can support surprisingly efficient negative selection of Ag-specific Thymocytes. Furthermore, we observe that agonist-dependent Thymocyte–Thymocyte interactions occurred as stable, motile conjugates led by the peptide-presenting Thymocyte and in which the trailing peptide-specific Thymocyte exhibited persistent elevations in intracellular calcium concentration. These data confirm that self-Ag presentation by Thymocytes is an additional mechanism to ensure T cell tolerance and further strengthen the correlation between stable cellular contacts, sustained TCR signals, and efficient negative selection.
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Tracking migration during human T cell development
Cellular and Molecular Life Sciences, 2014Co-Authors: Joanna Halkias, Heather J. Melichar, Kayleigh T. Taylor, Ellen A. RobeyAbstract:Specialized microenvironments within the thymus are comprised of unique cell types with distinct roles in directing the development of a diverse, functional, and self-tolerant T cell repertoire. As they differentiate, Thymocytes transit through a number of developmental intermediates that are associated with unique localization and migration patterns. For example, during one particular developmental transition, immature Thymocytes more than double in speed as they become mature T cells that are among the fastest cells in the body. This transition is associated with dramatic changes in the expression of chemokine receptors and their antagonists, cell adhesion molecules, and cytoskeletal components to direct the maturing Thymocyte population from the cortex to medulla. Here we discuss the dynamic changes in behavior that occur throughout Thymocyte development, and provide an overview of the cell-intrinsic and extrinsic mechanisms that regulate human Thymocyte migration.
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opposing chemokine gradients control human Thymocyte migration in situ
Journal of Clinical Investigation, 2013Co-Authors: Joanna Halkias, Heather J. Melichar, Jenny O. Ross, Kayleigh T. Taylor, Samantha B Cooper, Astar Winoto, Ellen A. RobeyAbstract:: The ordered migration of Thymocytes from the cortex to the medulla is critical for the appropriate selection of the mature T cell repertoire. Most studies of Thymocyte migration rely on mouse models, but we know relatively little about how human Thymocytes find their appropriate anatomical niches within the thymus. Moreover, the signals that retain CD4+CD8+ double-positive (DP) Thymocytes in the cortex and prevent them from entering the medulla prior to positive selection have not been identified in mice or humans. Here, we examined the intrathymic migration of human Thymocytes in both mouse and human thymic stroma and found that human Thymocyte subsets localized appropriately to the cortex on mouse thymic stroma and that MHC-dependent interactions between human Thymocytes and mouse stroma could maintain the activation and motility of DP cells. We also showed that CXCR4 was required to retain human DP Thymocytes in the cortex, whereas CCR7 promoted migration of mature human Thymocytes to the medulla. Thus, 2 opposing chemokine gradients control the migration of Thymocytes from the cortex to the medulla. These findings point to significant interspecies conservation in Thymocyte-stroma interactions and provide the first evidence that chemokines not only attract mature Thymocytes to the medulla, but also play an active role in retaining DP Thymocytes in the cortex prior to positive selection.
