The Experts below are selected from a list of 1920 Experts worldwide ranked by ideXlab platform
Yousuke Takahama - One of the best experts on this subject based on the ideXlab platform.
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Thymic nurse cells provide microenvironment for secondary t cell receptor α rearrangement in cortical thymocytes
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Yasushi Nakagawa, Takeshi Nitta, Shigeo Murata, Keiji Tanaka, Izumi Ohigashi, Mie Sakata, Osami Kanagawa, Yousuke TakahamaAbstract:Distinct subsets of Thymic epithelial cells (TECs) support T-cell development and selection. Isolated TECs contain multicellular complexes that enclose many viable thymocytes. However, the functions of those TECs, termed Thymic nurse cells (TNCs), are unclear and the idea that TNCs are present in vivo is questioned. Here, we show that TNCs represent a fraction of cortical (c)TECs that are defined by the expression of thymoproteasomes. Intravital imaging revealed TNCs in the Thymic Cortex in situ, whereas TNCs were detected neither during embryogenesis nor in the postnatal thymuses of various “positive-selector” T-cell receptor (TCR)-transgenic mice, indicating that TNCs are not essential for T-cell differentiation, including positive selection. Rather, cells within TNCs were enriched for long-lived CD4+CD8+ thymocytes that underwent secondary TCR-Vα rearrangement. Thus, TNC complexes are formed in vivo by persistent cTEC–thymocyte interactions that then provide a microenvironment that optimizes T-cell selection through secondary TCR rearrangement.
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Thymic epithelial cells working class heroes for t cell development and repertoire selection
Trends in Immunology, 2012Co-Authors: Graham Anderson, Yousuke TakahamaAbstract:The thymus represents an epithelial–mesenchymal tissue, anatomically structured into discrete cortical and medullary regions that contain phenotypically and functionally distinct stromal cells, as well as thymocytes at defined stages of maturation. The stepwise progression of thymocyte development seems to require serial migration through these distinct Thymic regions, where interactions with cortical Thymic epithelial cell (cTEC) and medullary Thymic epithelial cell (mTEC) subsets take place. Recent work on TEC subsets provides insight into T cell development and selection, such as the importance of tumour necrosis factor (TNF) receptor superfamily members in thymus medulla development, and the specialised antigen processing/presentation capacity of the Thymic Cortex for positive selection. Here, we summarise current knowledge on the development and function of the Thymic microenvironment, paying particular attention to the cortical and medullary epithelial compartments.
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role of Thymic Cortex specific self peptides in positive selection of t cells
Seminars in Immunology, 2010Co-Authors: Yousuke Takahama, Sachiko Nitta, Takeshi Nitta, Shigeo Murata, Adiratna Mat Ripen, Keiji TanakaAbstract:During T cell development in the thymus, a virgin repertoire of diverse TCRalphabeta recognition specificities in immature thymocytes is selected through positive and negative selection to form an immunocompetent and self-tolerant repertoire of mature T cells. Positive selection supports the survival of thymocytes that receive weak signals of low-avidity TCR engagement, whereas negative selection deletes potentially harmful self-reactive thymocytes upon high-avidity TCR engagement. Early studies have highlighted the role of TCR interaction with polymorphic MHC determinants in positive selection, while negative selection imposes TCR specificity to peptide antigens displayed by MHC molecules. However, recent advances in the biology of Thymic stromal cells have indicated that the formation of an immunocompetent TCR repertoire requires positive selection by Thymic cortical epithelial cells expressing a unique protein degradation machinery, suggesting the role of self-peptide repertoire specifically expressed by Thymic cortical epithelial cells in the development of the acquired immune system.
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CCR7-mediated migration of developing thymocytes to the medulla is essential for negative selection to tissue-restricted antigens.
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Takeshi Nitta, Sachiko Nitta, Martin Lipp, Yousuke TakahamaAbstract:Immature double-positive thymocytes are generated in the Thymic Cortex, and on positive selection, are induced to differentiate into mature single-positive thymocytes and relocate to the medulla. CCR7 is pivotal for Cortex-to-medulla migration of positively selected thymocytes, and CCR7-mediated migration to the medulla is essential for establishing central tolerance, thereby, preventing tissue-specific autoimmunity. However, it was unclear how CCR7-mediated migration to the medulla affects the establishment of self-tolerance. Here, we show that the deletion of thymocytes specific for insulin-promoter-driven tissue-restricted antigens (TRAs) is significantly impaired in CCR7- or CCR7-ligand-deficient mice. These results indicate that CCR7-mediated migration to the medulla contributes to the negative selection of TRA-reactive thymocytes.
Agustín G. Zapata - One of the best experts on this subject based on the ideXlab platform.
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FoxN1 mediates Thymic Cortex–medulla differentiation through modifying a developmental pattern based on epithelial tubulogenesis
Histochemistry and Cell Biology, 2019Co-Authors: Juan J Munoz, Esther Tobajas, Sonia Juara, Sara Montero, Agustín G. ZapataAbstract:The mechanisms that determine the commitment of Thymic epithelial precursors to the two major Thymic epithelial cell lineages, cTECs and mTECs, remain unknown. Here we show that FoxN1 nu mutation, which abolishes Thymic epithelium differentiation, results in the formation of a tubular branched structure according to a typical branching morphogenesis and tubulogenesis developmental pattern. In the presence of FoxN1, in alymphoid NSG and fetal Ikaros−/− thymi, there is no lumen formation and only partial apical differentiation. This initiates Cortex–medulla differentiation inducing expression of medullary genes in the apically differentiating cells and of cortical genes in the non-apically differentiating cells, which will definitely differentiate in wt and postnatal Ikaros−/− mice. Therefore, the thymus development is based on a branching morphogenesis and tubulogenesis developmental pattern: FoxN1 expression in the Thymic primordium inhibits tubulogenesis and induces the expression of genes involved in TEC differentiation, which culminates with the expression of functional cell markers, i.e., MHCII, CD80, Aire in both postnatal Ikaros−/− and WT thymi after arrival of lymphoid progenitor cells.
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Increased epithelial-free areas in thymuses with altered EphB-mediated thymocyte–Thymic epithelial cell interactions
Histochemistry and Cell Biology, 2017Co-Authors: Javier García-ceca, Sara Montero-herradón, David Alfaro, Agustín G. ZapataAbstract:Epithelial-free areas, present in both Thymic Cortex and medulla, have been studied in WT and EphB-deficient mice that have important alterations in the development of Thymic epithelium due to the lack of proper thymocyte–Thymic epithelial cell interactions. In both WT and mutant thymuses, the number and size of epithelial-free areas are significantly larger in the medulla than in the Cortex. The two parameters show a reverse correlation: low numbers of these areas course with large epithelial-free areas and vice versa. However, their structure and cell content are similar in mutant and WT thymuses. Cortical epithelial-free areas just contain DP thymocytes, while the medullary ones consist of SP cells, blood vessels, mesenchyme-derived ER-TR7^+ cells and components of the extracellular matrix (i.e., collagen IV, fibronectin, laminin). Other components, such as desmin, αSMA, PDGFRβ and Ng2, frequently associated with blood vessel walls, also appear. Vimentin, although present in medullary epithelial-free areas, does not co-express with epithelial cells. Other markers related to epithelial–mesenchymal transitions, such as Snail, Slug or FSP1, are not expressed. These results suggest that alterations in the cell interactions between distinct Thymic cell components that induce both increased proportions of apoptotic Thymic epithelial cells and altered behavior of the mesenchyme associated with the medullary vasculature could explain the appearance of these areas and their differences in the Cortex and medulla.
Juan J Munoz - One of the best experts on this subject based on the ideXlab platform.
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FoxN1 mediates Thymic Cortex–medulla differentiation through modifying a developmental pattern based on epithelial tubulogenesis
Histochemistry and Cell Biology, 2019Co-Authors: Juan J Munoz, Esther Tobajas, Sonia Juara, Sara Montero, Agustín G. ZapataAbstract:The mechanisms that determine the commitment of Thymic epithelial precursors to the two major Thymic epithelial cell lineages, cTECs and mTECs, remain unknown. Here we show that FoxN1 nu mutation, which abolishes Thymic epithelium differentiation, results in the formation of a tubular branched structure according to a typical branching morphogenesis and tubulogenesis developmental pattern. In the presence of FoxN1, in alymphoid NSG and fetal Ikaros−/− thymi, there is no lumen formation and only partial apical differentiation. This initiates Cortex–medulla differentiation inducing expression of medullary genes in the apically differentiating cells and of cortical genes in the non-apically differentiating cells, which will definitely differentiate in wt and postnatal Ikaros−/− mice. Therefore, the thymus development is based on a branching morphogenesis and tubulogenesis developmental pattern: FoxN1 expression in the Thymic primordium inhibits tubulogenesis and induces the expression of genes involved in TEC differentiation, which culminates with the expression of functional cell markers, i.e., MHCII, CD80, Aire in both postnatal Ikaros−/− and WT thymi after arrival of lymphoid progenitor cells.
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foxn1 mediates Thymic Cortex medulla differentiation through modifying a developmental pattern based on epithelial tubulogenesis
Histochemistry and Cell Biology, 2019Co-Authors: Juan J Munoz, Esther Tobajas, Sonia Juara, Sara Montero, A ZapataAbstract:The mechanisms that determine the commitment of Thymic epithelial precursors to the two major Thymic epithelial cell lineages, cTECs and mTECs, remain unknown. Here we show that FoxN1 nu mutation, which abolishes Thymic epithelium differentiation, results in the formation of a tubular branched structure according to a typical branching morphogenesis and tubulogenesis developmental pattern. In the presence of FoxN1, in alymphoid NSG and fetal Ikaros−/− thymi, there is no lumen formation and only partial apical differentiation. This initiates Cortex–medulla differentiation inducing expression of medullary genes in the apically differentiating cells and of cortical genes in the non-apically differentiating cells, which will definitely differentiate in wt and postnatal Ikaros−/− mice. Therefore, the thymus development is based on a branching morphogenesis and tubulogenesis developmental pattern: FoxN1 expression in the Thymic primordium inhibits tubulogenesis and induces the expression of genes involved in TEC differentiation, which culminates with the expression of functional cell markers, i.e., MHCII, CD80, Aire in both postnatal Ikaros−/− and WT thymi after arrival of lymphoid progenitor cells.
Kristin A Hogquist - One of the best experts on this subject based on the ideXlab platform.
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Thymic Selection: Getting out alive
2015Co-Authors: Kristin A Hogquist, Tom M Mccaughtry, Matt Wilken, Corey Carlson, Steve Jameson, Oludare OdumadeAbstract:Conventional αβ T cell precursors with a low affinity for self undergo positive selection in the Thymic Cortex, then migrate to the medulla. During their residency in the medulla, they undergo further maturation to become functionally responsive T cells, after which time they emigrate. In contrast to what was previously thought, we found that Thymic emigration occurs rapidly for conventional αβ T cells (1-2 days) and is dependent on the transcription factor KLF2. On the other hand long-lived antigen-experienced cells (NKT, Treg, memory cells etc.) can be found in the thymus, but this may reflect their re-circulation from the periphery. T cell precursors with a high affinity for self-antigens commonly die within the thymus—clonal deletion. We used a highly physiologic TCR transgenic model (HYcd4) to show that self-reactive thymocytes die in the Cortex. We also show that costimulatory molecules expressed in the medulla were dispensable for deletion, as was migration to the medulla or even an organized medullary epithelium. However, the kinetics of clonal deletion in vivo indicated that apoptosis was asynchronously activated over four days after receiving a high-affinity signal. This inefficient apoptosis mechanism may allo
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The Journal of Experimental Medicine CORRESPONDENCE
2013Co-Authors: Tom M Mccaughtry, Matthew S Wilken, Kristin A HogquistAbstract:Conventional � � T cell precursors undergo positive selection in the Thymic Cortex. When this is successful, they migrate to the medulla and are exposed to tissue-specific antigens (TSA) for purposes of central tolerance, and they undergo maturation to become functionally responsive T cells. It is commonly understood that thymocytes spend up to 2 wk in the medulla undergoing these final maturation steps before emigrating to peripheral lymphoid tissues. In addition, emigration is thought to occur via a stochastic mechanism whereby some progenitors leave early and others leave late — a so-called “ lucky dip ” process. However, recent research has revealed that medullary thymocytes are a heterogeneous mix of naive � � T cell precursors, memory T cells, natural killer T cells, and regulatory T cells. Given this, we revisited the question of how long it takes naive � � T cell precursors to emigrate. We combined the following three approaches to study this question: BrdU labeling, intraThymic injection of a cellular tag, and RAG2p-GFP reporter mice. We established that, on average, naive � � T cell precursors emigrate only 4 – 5 d after becoming singlepositive (SP) thymocytes. Furthermore, emigration occurs via a strict “ conveyor belt ” mechanism, where the oldest thymocytes leave first
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murine Thymic selection quantified using a unique method to capture deleted t cells
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Gretta L Stritesky, Yan Xing, Jami R Erickson, Lokesh A Kalekar, Xiaodan Wang, Daniel L Mueller, Stephen C Jameson, Kristin A HogquistAbstract:Thymic positive and negative selection events generate a T-cell repertoire that is MHC restricted and self-tolerant. The number of T cells undergoing positive and negative selection in normal mice has never been firmly established. We generated mice that lack the proapoptotic molecule Bim (bcl2l11) together with a Nur77GFP transgene, which allowed the identification and enumeration of T cells that would normally undergo clonal deletion. Using this method, we report the striking observation that six times more cells undergo negative selection than complete positive selection. Seventy-five percent of the negatively selected cells are deleted at the double positive stage in the Thymic Cortex, compared with 25% at the single positive stage in the medulla. The fact that more thymocytes are highly reactive to MHC than are weakly reactive is inconsistent with a random model of recognition and suggests that T-cell recognition is MHC biased. Furthermore, Bim−/− mice had an increased number of GFPhi cells in the peripheral lymphoid tissue and a corresponding increase in antigen experienced or anergic cell phenotype. Our data also show that the CD4+ T cells that are clonally deleted experienced only slightly stronger T-cell receptor signaling than those that developed into regulatory T cells.
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clonal deletion of thymocytes can occur in the Cortex with no involvement of the medulla
Journal of Experimental Medicine, 2008Co-Authors: Tom M Mccaughtry, Troy A Baldwin, Matthew S Wilken, Kristin A HogquistAbstract:The Thymic medulla is generally held to be a specialized environment for negative selection. However, many self-reactive thymocytes first encounter ubiquitous self-antigens in the Cortex. Cortical epithelial cells are vital for positive selection, but whether such cells can also promote negative selection is controversial. We used the HYcd4 model, where T cell receptor for antigen (TCR) expression is appropriately timed and a ubiquitous self-antigen drives clonal deletion in male mice. We demonstrated unambiguously that this deletion event occurs in the Thymic Cortex. However, the kinetics in vivo indicated that apoptosis was activated asynchronously relative to TCR activation. We found that radioresistant antigen-presenting cells and, specifically, cortical epithelial cells do not efficiently induce apoptosis, although they do cause TCR activation. Rather, thymocytes undergoing clonal deletion were preferentially associated with rare CD11c+ cortical dendritic cells, and elimination of such cells impaired deletion.
Henk-jan Schuurman - One of the best experts on this subject based on the ideXlab platform.
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Printed in the United States of America Epithelium-Free Area in the Thymic Cortex of Rats
2013Co-Authors: Joost P. Bruijntjes, Joke E. Robinson, Frieke C. Kuper, Henk-jan SchuurmanAbstract:The histology of epithelium-free areas in the subcapsular region of the thymus was studied in Wistar rats. Lymphocytes in these areas were CD4/CD8 double-positive, TCR c/]/positive in low intensity, and in CD5 labeling either negative or positive in low intensity. There was a high proliferative activity as assessed by bromodeoxyuridine incorporation in vivo and detected by immunohistochemistry. Various macrophage types were observed. They were either large and round to slightly dendritic, or small and dendritic. Most large cells were positive for MHC Class II, and labeled by the antimacrophage antibodies ED1 and ED2. A few cells were strongly positive for Sudan black, Oil red O, nonspecific esterase, and acid phosphatase; they resembled the large rounded macrophages in the corticomedullary zone, although their MHC Class II and ED2 staining was more intense. A few cells showed features of tingible body macrophages, as they contained cellular debris. Serial sections showed that epithelium-free areas run from the subcapsular area to deep in the Cortex, and often border the medulla. This opens the opportunity for immature lymphocytes to move into the medulla and corticomedullary zone without contacting and potential selection with cortical stromal elements other than macrophages in the epithelium-free areas. In this case, the epithelium-free areas may offer a separate intraThymic pathway for T lymphocytes
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Epithelium-free area in the Thymic Cortex of rats.
Developmental Immunology, 1993Co-Authors: Joost P. Bruijntjes, C. Frieke Kuper, Joke E. Robinson, Henk-jan SchuurmanAbstract:The histology of epithelium-free areas in the subcapsular region of the thymus was studied in Wistar rats. Lymphocytes in these areas were CD4/CD8 double-positive, TCR α/β positive in low intensity, and in CD5 labeling either negative or positive in low intensity. There was a high proliferative activity as assessed by bromodeoxyuridine incorporation in vivo and detected by immunohistochemistry. Various macrophage types were observed. They were either large and round to slightly dendritic, or small and dendritic. Most large cells were positive for MHC Class II, and labeled by the antimacrophage antibodies ED1 and ED2. A few cells were strongly positive for Sudan black, Oil red O, nonspecific esterase, and acid phosphatase; they resembled the large rounded macrophages in the corticomedullary zone, although their MHC Class II and ED2 staining was more intense. A few cells showed features of tingible body macrophages, as they contained cellular debris. Serial sections showed that epithelium-free areas run from the subcapsular area to deep in the Cortex, and often border the medulla. This opens the opportunity for immature lymphocytes to move into the medulla and corticomedullary zone without contacting and potential selection with cortical stromal elements other than macrophages in the epithelium-free areas. In this case, the epithelium-free areas may offer a separate intraThymic pathway for T lymphocytes.