The Experts below are selected from a list of 291 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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a role for pref 1 and hes 1 in thymocyte development
Journal of Immunology, 2000Co-Authors: Midori Kaneta, Kazuhiro Sudo, Yousuke Takahama, Masatake Osawa, Hiromitsu Nakauchi, Mitsujiro Osawa, Andrew G FarrAbstract:T lymphocyte development requires a series of interactions between developing Thymocytes and thymic epithelial (TE) cells. In this paper we show that TE cells in the developing thymus express Pref-1, a Delta-like cell-surface molecule. In fetal thymus organ cultures (FTOC), thymocyte cellularity was increased by the exogenous dimeric Pref-1 fusion protein, but was reduced by the soluble Pref-1 monomer or anti-Pref-1 Ab. Dimeric Pref-1 in FTOC also increased thymocyte expression of the HES-1 transcription factor. Thymocyte cellularity was increased in FTOC repopulated with immature Thymocytes overexpressing HES-1, whereas FTOC from HES-1-deficient mice were hypocellular and unresponsive to the Pref-1 dimer. We detected no effects of either Pref-1 or HES-1 on developmental choice among thymocyte lineages. These results indicate that Pref-1 expressed by TE cells and HES-1 expressed by Thymocytes are critically involved in supporting thymocyte cellularity.
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a role for pref 1 and hes 1 in thymocyte development
Journal of Immunology, 2000Co-Authors: Midori Kaneta, Kazuhiro Sudo, Yousuke Takahama, Masatake Osawa, Hiromitsu Nakauchi, Mitsujiro Osawa, Andrew G FarrAbstract:T lymphocyte development requires a series of interactions between developing Thymocytes and thymic epithelial (TE) cells. In this paper we show that TE cells in the developing thymus express Pref-1, a Delta-like cell-surface molecule. In fetal thymus organ cultures (FTOC), thymocyte cellularity was increased by the exogenous dimeric Pref-1 fusion protein, but was reduced by the soluble Pref-1 monomer or anti-Pref-1 Ab. Dimeric Pref-1 in FTOC also increased thymocyte expression of the HES-1 transcription factor. Thymocyte cellularity was increased in FTOC repopulated with immature Thymocytes overexpressing HES-1, whereas FTOC from HES-1-deficient mice were hypocellular and unresponsive to the Pref-1 dimer. We detected no effects of either Pref-1 or HES-1 on developmental choice among thymocyte lineages. These results indicate that Pref-1 expressed by TE cells and HES-1 expressed by Thymocytes are critically involved in supporting thymocyte cellularity.
Hidde L Ploegh - One of the best experts on this subject based on the ideXlab platform.
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The ubiquitin-proteasome pathway in thymocyte apoptosis: caspase-dependent processing of the deubiquitinating enzyme USP7 (HAUSP).
Molecular Immunology, 2002Co-Authors: Yulia Vugmeyster, Anna Borodovsky, Madelon M. Maurice, René Maehr, Margo H. Furman, Hidde L PloeghAbstract:Abstract Programmed cell death (apoptosis) is crucial for thymocyte development. We analyzed the role of the ubiquitin (Ub)–proteasome pathway in dexamethasone-triggered and TCR-mediated apoptosis in fetal thymic organ culture (FTOC). Proteasome activity was increased in apoptotic Thymocytes, as visualized by active-site labeling of proteasomal β subunits. The activity of deubiquitinating enzymes in murine apoptotic Thymocytes was likewise examined by active-site labeling. We show that the deubiquitinating enzyme USP7 (HAUSP) is proteolytically processed upon dexamethasone-, γ-irradiation-, and antigen-induced cell death. Such processing of HAUSP does not occur in caspase 3 −/− Thymocytes, or upon pretreatment of wild type Thymocytes with the general caspase inhibitor ZVAD-fmk. Thus, our results suggest that thymocyte apoptosis leads to modification of deubiquitinating enzymes by caspase activity and may provide an additional link between the ubiquitin–proteasome pathway and the caspase cascade during programmed cell death.
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The ubiquitin-proteasome pathway in thymocyte apoptosis: caspase-dependent processing of the deubiquitinating enzyme USP7 (HAUSP).
Molecular immunology, 2002Co-Authors: Yulia Vugmeyster, Anna Borodovsky, Madelon M. Maurice, René Maehr, Margo H. Furman, Hidde L PloeghAbstract:Programmed cell death (apoptosis) is crucial for thymocyte development. We analyzed the role of the ubiquitin (Ub)-proteasome pathway in dexamethasone-triggered and TCR-mediated apoptosis in fetal thymic organ culture (FTOC). Proteasome activity was increased in apoptotic Thymocytes, as visualized by active-site labeling of proteasomal beta subunits. The activity of deubiquitinating enzymes in murine apoptotic Thymocytes was likewise examined by active-site labeling. We show that the deubiquitinating enzyme USP7 (HAUSP) is proteolytically processed upon dexamethasone-, gamma-irradiation-, and antigen-induced cell death. Such processing of HAUSP does not occur in caspase 3-/- Thymocytes, or upon pretreatment of wild type Thymocytes with the general caspase inhibitor ZVAD-fmk. Thus, our results suggest that thymocyte apoptosis leads to modification of deubiquitinating enzymes by caspase activity and may provide an additional link between the ubiquitin-proteasome pathway and the caspase cascade during programmed cell death.
Paul E. Love - One of the best experts on this subject based on the ideXlab platform.
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Targeted Sos1 deletion reveals its critical role in early T-cell development
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Robert L. Kortum, Connie L. Sommers, Clayton P. Alexander, John M. Pinski, Alex Grinberg, Jan Lee, Paul E. Love, Lawrence E. SamelsonAbstract:Activation of the small G protein Ras is required for thymocyte differentiation. In Thymocytes, Ras is activated by the Ras guanine exchange factors (RasGEFs) Sos1, Sos2, and RasGRP1. We report the development of a floxed allele of sos1 to assess the role of Sos1 during thymocyte development. Sos1 was required for pre–T-cell receptor (pre-TCR)– but not TCR-stimulated developmental signals. Sos1 deletion led to a partial block at the DN-to-DP transition. Sos1-deficient Thymocytes showed reduced pre-TCR–stimulated proliferation, differentiation, and ERK phosphorylation. In contrast, TCR-stimulated positive selection, and negative selection under strong stimulatory conditions, remained intact in Sos1-deficient mice. Comparison of RasGEF expression at different developmental stages showed that relative to Sos2 and RasGRP1, Sos1 is most abundant in DN Thymocytes, but least abundant in DP Thymocytes. These data reveal that Sos1 is uniquely positioned to affect signal transduction early in thymocyte development.
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Premature expression of chemokine receptor CCR9 impairs T cell development.
Journal of immunology (Baltimore Md. : 1950), 2005Co-Authors: Shoji Uehara, Dalal El-khoury, Matilde Canelles, B. J. Fowlkes, Sandra M. Hayes, Paul E. LoveAbstract:During thymocyte development, CCR9 is expressed on late CD4-CD8- (double-negative (DN)) and CD4+CD8+ (double-positive) cells, but is subsequently down-regulated as cells transition to the mature CD4+ or CD8+ (single-positive (SP)) stage. This pattern of expression has led to speculation that CCR9 may regulate thymocyte trafficking and/or export. In this study, we generated transgenic mice in which CCR9 surface expression was maintained throughout T cell development. Significantly, forced expression of CCR9 on mature SP Thymocytes did not inhibit their export from the thymus, indicating that CCR9 down-regulation is not essential for thymocyte emigration. CCR9 was also expressed prematurely on immature DN Thymocytes in CCR9 transgenic mice. Early expression of CCR9 resulted in a partial block of development at the DN stage and a marked reduction in the numbers of double-positive and SP Thymocytes. Moreover, in CCR9-transgenic mice, CD25high DN cells were scattered throughout the cortex rather than confined to the subcapsular region of the thymus. Together, these results suggest that regulated expression of CCR9 is critical for normal development of immature Thymocytes, but that down-regulation of CCR9 is not a prerequisite for thymocyte emigration.
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A potential role for CD69 in thymocyte emigration
International immunology, 2002Co-Authors: Chiguang Feng, Jan Lee, Barbara A. Vance, Kenneth J. Woodside, Dalal El-khoury, Matilde Canelles, Ronald E. Gress, B. J. Fowlkes, Elizabeth W. Shores, Paul E. LoveAbstract:The early activation marker, CD69, is transiently expressed on activated mature T cells and on Thymocytes that are undergoing positive or negative selection in the thymus. CD69 is a member of the NK gene complex family of C-type lectin-like signaling receptors; however, its function is unknown. In this report, we describe the characterization of mice that constitutively express high levels of surface CD69 on immature and mature T cells throughout development. Constitutive surface expression of CD69 did not affect T cell maturation, signaling through the TCR or thymocyte selection. However, phenotypically and functionally mature Thymocytes accumulated in the medulla of CD69 transgenic mice and failed to be exported from the thymus. The retention of mature Thymocytes correlated with transgene dose and CD69 surface levels. These results identify a potential role for CD69 in controlling thymocyte export, and suggest that the transient expression of CD69 on Thymocytes and T cells may function to regulate thymocyte and T cell trafficking.
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Characterization of CCR9 Expression and CCL25/Thymus-Expressed Chemokine Responsiveness During T Cell Development: CD3highCD69+ Thymocytes and γδTCR+ Thymocytes Preferentially Respond to CCL25
Journal of immunology (Baltimore Md. : 1950), 2002Co-Authors: Shoji Uehara, Kaimei Song, Joshua M. Farber, Paul E. LoveAbstract:CCR9 mediates chemotaxis of Thymocytes in response to CCL25/thymus-expressed chemokine, and its mRNA is selectively expressed in thymus and small intestine, the two known sites of T lymphopoiesis. To examine the expression of CCR9 during lymphocyte development, we generated polyclonal Ab that recognizes murine CCR9. CCR9 was expressed on the majority of immature CD4+CD8+ (double-positive) Thymocytes, but not on immature CD4−CD8− (double-negative) Thymocytes. CCR9 was down-regulated during the transition of double-positive Thymocytes to the CD4+ or CD8+ (single-positive) stage, and only a minor subset of CD8+ lymph node T cells expressed CCR9. All CCR9+ thymocyte subsets migrated in response to CCL25; however, CD69+ Thymocytes demonstrated enhanced CCL25-induced migration compared with CD69− Thymocytes. Ab-mediated TCR stimulation also enhanced CCL25 responsiveness, indicating that CCL25-induced thymocyte migration is augmented by TCR signaling. Approximately one-half of all γδTCR+ Thymocytes and peripheral γδTCR+ T cells expressed CCR9 on their surface, and these cells migrated in response to CCL25. These findings suggest that CCR9 may play an important role in the development and trafficking of both αβTCR+ and γδTCR+ T cells.
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characterization of ccr9 expression and ccl25 thymus expressed chemokine responsiveness during t cell development cd3highcd69 Thymocytes and γδtcr Thymocytes preferentially respond to ccl25
Journal of Immunology, 2002Co-Authors: Shoji Uehara, Kaimei Song, Joshua M. Farber, Paul E. LoveAbstract:CCR9 mediates chemotaxis of Thymocytes in response to CCL25/thymus-expressed chemokine, and its mRNA is selectively expressed in thymus and small intestine, the two known sites of T lymphopoiesis. To examine the expression of CCR9 during lymphocyte development, we generated polyclonal Ab that recognizes murine CCR9. CCR9 was expressed on the majority of immature CD4+CD8+ (double-positive) Thymocytes, but not on immature CD4−CD8− (double-negative) Thymocytes. CCR9 was down-regulated during the transition of double-positive Thymocytes to the CD4+ or CD8+ (single-positive) stage, and only a minor subset of CD8+ lymph node T cells expressed CCR9. All CCR9+ thymocyte subsets migrated in response to CCL25; however, CD69+ Thymocytes demonstrated enhanced CCL25-induced migration compared with CD69− Thymocytes. Ab-mediated TCR stimulation also enhanced CCL25 responsiveness, indicating that CCL25-induced thymocyte migration is augmented by TCR signaling. Approximately one-half of all γδTCR+ Thymocytes and peripheral γδTCR+ T cells expressed CCR9 on their surface, and these cells migrated in response to CCL25. These findings suggest that CCR9 may play an important role in the development and trafficking of both αβTCR+ and γδTCR+ T cells.
Walter Witke - One of the best experts on this subject based on the ideXlab platform.
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Cofilin1 driven actin dynamics controls migration of Thymocytes and is essential for positive selection in the thymus
Journal of Cell Science, 2020Co-Authors: Andree Salz, Christine Gurniak, Friederike Jönsson, Walter WitkeAbstract:Actin dynamics is essential for T cell development. We show here that cofilin1 is the key molecule for controlling actin filament turnover in this process. Mice with specific depletion of cofilin1 in Thymocytes showed increased steady state levels of actin filaments, and associated alterations in the pattern of thymocyte migration and adhesion. Our data suggest that cofilin1 is controlling oscillatory F-actin changes, a parameter that influences the migration pattern in a 3-D environment. In a collagen matrix, cofilin1 controls the speed and resting intervals of migrating Thymocytes. Cofilin1 was not involved in thymocyte proliferation, cell survival, apoptosis, or surface receptor trafficking. However, in cofilin1 mutant mice impaired adhesion and migration resulted in a specific block of thymocyte differentiation from CD4/CD8 double positive Thymocytes towards CD4 and CD8 single positive cells. Our data suggest that tuning of the dwelling time of Thymocytes in the thymic niches is tightly controlled by cofilin1 and essential for positive selection during T cell differentiation. We describe a novel role of cofilin1 in the physiological context of migration dependent cell differentiation.
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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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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dynamics of thymocyte stromal cell interactions visualized by two photon microscopy
Science, 2002Co-Authors: Philippe Bousso, Nirav R Bhakta, Richard S Lewis, Ellen A. RobeyAbstract:Thymocytes are selected to mature according to their ability to interact with self major histocompatibility complex (MHC)–peptide complexes displayed on the thymic stroma. Using two-photon microscopy, we performed real-time analysis of the cellular contacts made by developing Thymocytes undergoing positive selection in a three-dimensional thymic organ culture. A large fraction of Thymocytes within these cultures were highly motile. MHC recognition was found to increase the duration of thymocyte–stromal cell interactions and occurred as both long-lived cellular associations displaying stable cell-cell contacts and as shorter, highly dynamic contacts. Our results identify the diversity and dynamics of thymocyte interactions during positive selection.
