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Eric J Jenkinson - One of the best experts on this subject based on the ideXlab platform.
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differential requirement for ccr4 and ccr7 during the development of innate and adaptive αβt cells in the adult thymus
Journal of Immunology, 2014Co-Authors: Jennifer E Cowan, Arnauld Sergé, Magali Irla, Sonia M Parnell, Peter J L Lane, Eric J Jenkinson, Nicholas I Mccarthy, Andrea J White, Andrea Bacon, William E JenkinsonAbstract:αβT cell development depends upon serial migration of thymocyte precursors through cortical and Medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional αβT cells are subject to clonal deletion in the Medulla, entry into the thymus Medulla also fosters αβT cell differentiation. For example, during postnatal periods, the Medulla is involved in the intraThymic generation of multiple αβT cell lineages, notably the induction of Foxp3+ regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional αβT cells to the Medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to Medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple αβT cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire−/− mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the Thymic Medulla and influences the balance of early and late intraThymic stages of Foxp3+ regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intraThymic T cell development, highlighting its importance in enabling multiple αβT cell lineages to access the Thymic Medulla.
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the Thymic Medulla is required for foxp3 regulatory but not conventional cd4 thymocyte development
Journal of Experimental Medicine, 2013Co-Authors: Jennifer E Cowan, Sonia M Parnell, Kyoko Nakamura, Jorge Caamano, Peter J L Lane, Eric J Jenkinson, William E Jenkinson, Graham AndersonAbstract:A key role of the Thymic Medulla is to negatively select autoreactive CD4+ and CD8+ thymocytes, a process important for T cell tolerance induction. However, the involvement of the Thymic Medulla in other aspects of αβ T cell development, including the generation of Foxp3+ natural regulatory T cells (nTreg cells) and the continued maturation of positively selected conventional αβ T cells, is unclear. We show that newly generated conventional CD69+Qa2− CD4 single-positive thymocytes mature to the late CD69−Qa2+ stage in the absence of RelB-dependent Medullary Thymic epithelial cells (mTECs). Furthermore, an increasing ability to continue maturation extraThymically is observed within the CD69+CCR7−/loCCR9+ subset of conventional SP4 thymocytes, providing evidence for an independence from Medullary support by the earliest stages after positive selection. In contrast, Foxp3+ nTreg cell development is Medullary dependent, with mTECs fostering the generation of Foxp3−CD25+ nTreg cell precursors at the CD69+CCR7+CCR9− stage. Our results demonstrate a differential requirement for the Thymic Medulla in relation to CD4 conventional and Foxp3+ thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3+ nTreg cell development through the generation of Foxp3−CD25+ nTreg cell precursors.
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Aire is not Required for Vγ5+ DETC Progenitor Clustering with mTEC.
2013Co-Authors: Kyoko Nakamura, Sonia M Parnell, Eric J Jenkinson, William E Jenkinson, Andrea J White, Peter J. Lane, Graham AndersonAbstract:(A) Representative confocal analysis of E18 WT and Aire−/− thymus sections. Vγ5+ cells are shown in green, CD8β+ cells are shown in red and EpCAM+ Medullary areas are shown in blue. M denotes Medulla, C denotes cortex. Scale bars in A represent 100 µm. (B) Quantification of Vγ5+ cells per mm2 Thymic Medulla. WT; n = 6, Aire−/−; n = 6. Error bars represents SEM. (C) Individual thymus lobes of E18 WT and Aire−/− embryos were teased apart and stained for Vγ5, CD3, CD24 and CD45RB expression. Numbers shown on FACS plot are the mean percentages +/− SD. WT; n = 9, Aire−/−; n = 4.
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mechanisms of thymus Medulla development and function
Current Topics in Microbiology and Immunology, 2013Co-Authors: Graham Anderson, Jennifer E Cowan, Sonia M Parnell, Kyoko Nakamura, Peter J L Lane, Nicholas I Mccarthy, Song Baik, Andrea J White, Amanda M Holland, Eric J JenkinsonAbstract:The development of CD4+ helper and CD8+ cytotoxic T-cells expressing the αβ form of the T-cell receptor (αβTCR) takes place in the thymus, a primary lymphoid organ containing distinct cortical and Medullary microenvironments. While the cortex represents a site of early T-cell precursor development, and the positive selection of CD4+8+ thymocytes, the Thymic Medulla plays a key role in tolerance induction, ensuring that Thymic emigrants are purged of autoreactive αβTCR specificities. In recent years, advances have been made in understanding the development and function of Thymic Medullary epithelial cells, most notably the subset defined by expression of the Autoimmune Regulator (Aire) gene. Here, we summarize current knowledge of the developmental mechanisms regulating thymus Medulla development, and examine the role of the thymus Medulla in recessive (negative selection) and dominant (T-regulatory cell) tolerance.
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rank signals from cd4 3 inducer cells regulate development of aire expressing epithelial cells in the Thymic Medulla
Journal of Experimental Medicine, 2007Co-Authors: Simona W Rossi, Sonia M Parnell, William E Jenkinson, Miyeon Kim, Andreas Leibbrandt, Stephanie H Glanville, Fiona M Mcconnell, Hamish S Scott, Josef M Penninger, Eric J JenkinsonAbstract:Aire-expressing Medullary Thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient Thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intraThymic self-tolerance.
Izumi Ohigashi - One of the best experts on this subject based on the ideXlab platform.
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essential role of ccl21 in establishment of central self tolerance in t cells
Journal of Experimental Medicine, 2017Co-Authors: Mina Kozai, Izumi Ohigashi, Naozumi Ishimaru, Yuki Kubo, Tomoya Katakai, Hiroyuki Kondo, Hiroshi Kiyonari, Karin Schaeuble, Sanjiv A Luther, Yousuke TakahamaAbstract:The chemokine receptor CCR7 directs T cell relocation into and within lymphoid organs, including the migration of developing thymocytes into the Thymic Medulla. However, how three functional CCR7 ligands in mouse, CCL19, CCL21Ser, and CCL21Leu, divide their roles in immune organs is unclear. By producing mice specifically deficient in CCL21Ser, we show that CCL21Ser is essential for the accumulation of positively selected thymocytes in the Thymic Medulla. CCL21Ser-deficient mice were impaired in the Medullary deletion of self-reactive thymocytes and developed autoimmune dacryoadenitis. T cell accumulation in the lymph nodes was also defective. These results indicate a nonredundant role of CCL21Ser in the establishment of self-tolerance in T cells in the Thymic Medulla, and reveal a functional inequality among CCR7 ligands in vivo.
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dynamic spatio temporal contribution of single β5t cortical epithelial precursors to the thymus Medulla
European Journal of Immunology, 2016Co-Authors: Carlos E Mayer, Izumi Ohigashi, Saulius žuklys, Saule Zhanybekova, Hongying Teh, Stephen N Sansom, Noriko Shikamadorn, Katrin Hafen, Iain C Macaulay, Mary E DeadmanAbstract:IntraThymic T-cell development is critically dependent on cortical and Medullary Thymic epithelial cells (TECs). Both epithelial subsets originate during early thymus organogenesis from progenitor cells that express the thymoproteasome subunit β5t, a typical feature of cortical TECs. Using in vivo lineage fate mapping, we demonstrate in mice that β5t(+) TEC progenitors give rise to the Medullary TEC compartment early in life but significantly limit their contribution once the Medulla has completely formed. Lineage-tracing studies at single cell resolution demonstrate for young mice that the postnatal Medulla is expanded from individual β5t(+) cortical progenitors located at the cortico-Medullary junction. These results therefore not only define a developmental window during which the expansion of Medulla is efficiently enabled by progenitors resident in the Thymic cortex, but also reveal the spatio-temporal dynamics that control the growth of the Thymic Medulla.
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Effects of RANKL on the Thymic Medulla.
European journal of immunology, 2011Co-Authors: Izumi Ohigashi, Takeshi Nitta, Enkhsaikhan Lkhagvasuren, Hisataka Yasuda, Yousuke TakahamaAbstract:The Thymic Medulla provides a microenvironment where Medullary Thymic epithelial cells (mTECs) contribute to the establishment of self-tolerance by the deletion of self-reactive T cells and the generation of regulatory T cells. The progression of thymocyte development critically regulates the optimum formation of the Thymic Medulla, as discussed in this article. Of note, it was recently identified that RANKL produced by positively selected thymocytes plays a major role in the thymocyte-mediated Medulla formation. Indeed, transgenic expression of soluble RANKL increased the number of mTECs and enlarged the Thymic Medulla in mice. The effects of RANKL on the Thymic Medulla may be useful for the engineering of self-tolerance in T cells.
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cytokine crosstalk for Thymic Medulla formation
Current Opinion in Immunology, 2011Co-Authors: Takeshi Nitta, Izumi Ohigashi, Yasushi Nakagawa, Yousuke TakahamaAbstract:The Medullary microenvironment of the thymus plays a crucial role in the establishment of self-tolerance through the deletion of self-reactive thymocytes and the generation of regulatory T cells. Crosstalk or bidirectional signal exchanges between developing thymocytes and Medullary Thymic epithelial cells (mTECs) contribute to the formation of the Thymic Medulla. Recent studies have identified the molecules that mediate Thymic crosstalk. Tumor necrosis factor superfamily cytokines, including RANKL, CD40L, and lymphotoxin, produced by positively selected thymocytes and lymphoid tissue inducer cells promote the proliferation and differentiation of mTECs. In return, CCR7 ligand chemokines produced by mTECs facilitate the migration of positively selected thymocytes to the Medulla. The cytokine crosstalk between developing thymocytes and mTECs nurtures the formation of the Thymic Medulla and thereby regulates the establishment of self-tolerance.
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the cytokine rankl produced by positively selected thymocytes fosters Medullary Thymic epithelial cells that express autoimmune regulator
Immunity, 2008Co-Authors: Yu Hikosaka, Takeshi Nitta, Izumi Ohigashi, Kouta Yano, Yoshio Hayashi, Mitsuru Matsumoto, Joseph M. Penninger, Koichi Matsuo, Naozumi Ishimaru, Hiroshi TakayanagiAbstract:The Thymic Medulla provides a microenvironment where Medullary Thymic epithelial cells (mTECs) express autoimmune regulator and diverse tissue-restricted genes, contributing to launching self-tolerance. Positive selection is essential for Thymic Medulla formation via a previously unknown mechanism. Here we show that the cytokine RANK ligand (RANKL) was produced by positively selected thymocytes and regulated the cellularity of mTEC by interacting with RANK and osteoprotegerin. Forced expression of RANKL restored Thymic Medulla in mice lacking positive selection, whereas RANKL perturbation impaired Medulla formation. These results indicate that RANKL produced by positively selected thymocytes is responsible for fostering Thymic Medulla formation, thereby establishing central tolerance.
Graham Anderson - One of the best experts on this subject based on the ideXlab platform.
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Image_1_Increased Production of IL-17A-Producing γδ T Cells in the Thymus of Filaggrin-Deficient Mice.jpg
2018Co-Authors: Mia Hamilton Jee, Jeanne Duus Johansen, Terkild Brink Buus, Trine Hilkjær Petersen, Anne-sofie Østergaard Gadsbøll, Anders Woetmann, Niels Ødum, Jacob Pontoppidan Thyssen, Andrea Jane White, Graham AndersonAbstract:Mutations in the filaggrin gene (Flg) are associated with increased systemic levels of Th17 cells and increased IL-17A production following antigen exposure in both humans and mice. In addition to Th17 cells, γδ T cells can produce IL-17A. The differentiation of γδ T cells to either IFNγ or IL-17A-producing (γδT17) cells is mainly determined in the thymus. Interestingly, it has been reported that filaggrin is expressed in the Hassall bodies in the human Thymic Medulla. However, whether filaggrin affects γδ T cell development is not known. Here, we show that filaggrin-deficient flaky tail (ft/ft) mice have an increased number of γδT17 cells in the spleen, epidermis, and thymus compared to wild-type (WT) mice. We demonstrate that filaggrin is expressed in the mouse Thymic Medulla and that blocking the egress of cells from the thymus results in accumulation of Vγ2+ γδT17 cells in the thymus of adult ft/ft mice. Finally, we find increased T cell receptor expression levels on γδ T cells and increased levels of IL-6 and IL-23 in the thymus of ft/ft mice. These findings demonstrate that filaggrin is expressed in the mouse Thymic Medulla and that production of Vγ2+ γδT17 cells is dysregulated in filaggrin-deficient ft/ft mice.
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control of the Thymic Medulla and its influence on αβt cell development
Immunological Reviews, 2016Co-Authors: Beth Lucas, Sonia M Parnell, William E Jenkinson, Nicholas I Mccarthy, Song Baik, Emilie J Cosway, Kieran D James, Andrea J White, Graham AndersonAbstract:The thymus is a primary lymphoid tissue that supports the generation of αβT cells. In this review, we describe the processes that give rise to the thymus Medulla, a site that nurtures self-tolerant T-cell generation following positive selection events that take place in the cortex. To summarize the developmental pathways that generate Medullary Thymic epithelial cells (mTEC) from their immature progenitors, we describe work on both the initial emergence of the Medulla during embryogenesis, and the maintenance of the Medulla during postnatal stages. We also investigate the varying roles that receptors belonging to the tumor necrosis factor receptor superfamily have on thymus Medulla development and formation, and highlight the impact that T-cell development has on thymus Medulla formation. Finally, we examine the evidence that the Thymic Medulla plays an important role during the intraThymic generation of distinct αβT-cell subtypes. Collectively, these studies provide new insight into the development and functional importance of Medullary microenvironments during self-tolerant T-cell production in the thymus.
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the Thymic Medulla is required for foxp3 regulatory but not conventional cd4 thymocyte development
Journal of Experimental Medicine, 2013Co-Authors: Jennifer E Cowan, Sonia M Parnell, Kyoko Nakamura, Jorge Caamano, Peter J L Lane, Eric J Jenkinson, William E Jenkinson, Graham AndersonAbstract:A key role of the Thymic Medulla is to negatively select autoreactive CD4+ and CD8+ thymocytes, a process important for T cell tolerance induction. However, the involvement of the Thymic Medulla in other aspects of αβ T cell development, including the generation of Foxp3+ natural regulatory T cells (nTreg cells) and the continued maturation of positively selected conventional αβ T cells, is unclear. We show that newly generated conventional CD69+Qa2− CD4 single-positive thymocytes mature to the late CD69−Qa2+ stage in the absence of RelB-dependent Medullary Thymic epithelial cells (mTECs). Furthermore, an increasing ability to continue maturation extraThymically is observed within the CD69+CCR7−/loCCR9+ subset of conventional SP4 thymocytes, providing evidence for an independence from Medullary support by the earliest stages after positive selection. In contrast, Foxp3+ nTreg cell development is Medullary dependent, with mTECs fostering the generation of Foxp3−CD25+ nTreg cell precursors at the CD69+CCR7+CCR9− stage. Our results demonstrate a differential requirement for the Thymic Medulla in relation to CD4 conventional and Foxp3+ thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3+ nTreg cell development through the generation of Foxp3−CD25+ nTreg cell precursors.
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Aire is not Required for Vγ5+ DETC Progenitor Clustering with mTEC.
2013Co-Authors: Kyoko Nakamura, Sonia M Parnell, Eric J Jenkinson, William E Jenkinson, Andrea J White, Peter J. Lane, Graham AndersonAbstract:(A) Representative confocal analysis of E18 WT and Aire−/− thymus sections. Vγ5+ cells are shown in green, CD8β+ cells are shown in red and EpCAM+ Medullary areas are shown in blue. M denotes Medulla, C denotes cortex. Scale bars in A represent 100 µm. (B) Quantification of Vγ5+ cells per mm2 Thymic Medulla. WT; n = 6, Aire−/−; n = 6. Error bars represents SEM. (C) Individual thymus lobes of E18 WT and Aire−/− embryos were teased apart and stained for Vγ5, CD3, CD24 and CD45RB expression. Numbers shown on FACS plot are the mean percentages +/− SD. WT; n = 9, Aire−/−; n = 4.
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mechanisms of thymus Medulla development and function
Current Topics in Microbiology and Immunology, 2013Co-Authors: Graham Anderson, Jennifer E Cowan, Sonia M Parnell, Kyoko Nakamura, Peter J L Lane, Nicholas I Mccarthy, Song Baik, Andrea J White, Amanda M Holland, Eric J JenkinsonAbstract:The development of CD4+ helper and CD8+ cytotoxic T-cells expressing the αβ form of the T-cell receptor (αβTCR) takes place in the thymus, a primary lymphoid organ containing distinct cortical and Medullary microenvironments. While the cortex represents a site of early T-cell precursor development, and the positive selection of CD4+8+ thymocytes, the Thymic Medulla plays a key role in tolerance induction, ensuring that Thymic emigrants are purged of autoreactive αβTCR specificities. In recent years, advances have been made in understanding the development and function of Thymic Medullary epithelial cells, most notably the subset defined by expression of the Autoimmune Regulator (Aire) gene. Here, we summarize current knowledge of the developmental mechanisms regulating thymus Medulla development, and examine the role of the thymus Medulla in recessive (negative selection) and dominant (T-regulatory cell) tolerance.
Terri M Laufer - One of the best experts on this subject based on the ideXlab platform.
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subcellular distribution of lck during cd4 t cell maturation in the Thymic Medulla regulates the t cell activation threshold
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Tom L Stephen, Bridget S Wilson, Terri M LauferAbstract:Mature peripheral T cells respond to foreign but not to self-antigens. During development in the thymus, deletion of high-affinity self-reactive immature thymocytes contributes to tolerance of mature T cells. However, double-positive thymocytes are positively selected to survive if they respond to self-peptide–MHC complexes; thus, there must be mechanisms to prevent overt reactivity to those same complexes in the periphery. “Developmental tuning” is the active process through which T-cell receptor (TCR)-associated signaling pathways of single-positive (SP) thymocytes are attenuated to respond appropriately to self-peptide–MHC complexes in the periphery. We previously showed that MHC class II expression in the Thymic Medulla was necessary to tune CD4+ SP (CD4 SP) thymocytes. CD4 SP thymocytes from mice lacking Medullary MHC class II expression had inappropriately enhanced proximal TCR signaling to low-affinity self-ligands that was associated with altered cellular distribution of the tyrosine kinase Lck. Now, we report that activation of both tuned and untuned CD4 SP thymocytes is Lck-dependent. Untuned CD4 SP cells contain a pool of Lck with increased basal phosphorylation that is not associated with the CD4 coreceptor. Phosphorylation of this pool of Lck decreases with tuning. Immunogold transmission electron microscopy of membrane sheets permitted direct visualization of Lck. In the absence of tuning, a significant proportion of Lck and the TCR subunit CD3ζ are expressed on the same protein island; this close association of Lck and the TCR probably explains the enhanced activation of untuned CD4 SP cells. Thus, changes in membrane topography during Thymic maturation determine the set point for TCR responsiveness.
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the activation threshold of cd4 t cells is defined by tcr peptide mhc class ii interactions in the Thymic Medulla
Journal of Immunology, 2009Co-Authors: Tom L Stephen, Anastasia N Tikhonova, Janice M Riberdy, Terri M LauferAbstract:Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4(+) single-positive T cells to MHC class II encountered in the Thymic Medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either Thymic Medullary epithelial cells or Thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class II and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4(+) T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on Thymic Medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire.
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developmental alterations in thymocyte sensitivity are actively regulated by mhc class ii expression in the Thymic Medulla
Journal of Immunology, 2006Co-Authors: Steven C Eck, Peimin Zhu, Marion Pepper, Steven J Bensinger, Bruce D Freedman, Terri M LauferAbstract:Developing thymocytes are positively selected if they respond to self-MHC-peptide complexes, yet mature T cells are not activated by those same self-complexes. To avoid autoimmunity, positive selection must be followed by a period of maturation when the cellular response to TCR signals is altered. The mechanisms that mediate this postselection developmental tuning remain largely unknown. Specifically, it is unknown whether developmental tuning is a preprogrammed outcome of positive selection or if it is sensitive to ongoing interactions between the thymocyte and the Thymic stroma. We probed the requirement for MHC class II-TCR interactions in postselection maturation by studying single positive (SP) CD4 thymocytes from K14/A β b mice, in which CD4 T cells cannot interact with MHC class II in the Thymic Medulla. We report here that SP CD4 thymocytes must receive MHC class II signals to avoid hyperactive responses to TCR signals. This hyperactivity correlates with decreased expression of CD5; however, developmental tuning can occur independently of CD5, correlating instead with differences in the distribution of Lck. Thus, the maturation of postselection SP CD4 thymocytes is an active process mediated by ongoing interactions between the T cell and MHC class II molecules. This represents a novel mechanism by which the Thymic Medulla prevents autoreactivity.
William E Jenkinson - One of the best experts on this subject based on the ideXlab platform.
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control of the Thymic Medulla and its influence on αβt cell development
Immunological Reviews, 2016Co-Authors: Beth Lucas, Sonia M Parnell, William E Jenkinson, Nicholas I Mccarthy, Song Baik, Emilie J Cosway, Kieran D James, Andrea J White, Graham AndersonAbstract:The thymus is a primary lymphoid tissue that supports the generation of αβT cells. In this review, we describe the processes that give rise to the thymus Medulla, a site that nurtures self-tolerant T-cell generation following positive selection events that take place in the cortex. To summarize the developmental pathways that generate Medullary Thymic epithelial cells (mTEC) from their immature progenitors, we describe work on both the initial emergence of the Medulla during embryogenesis, and the maintenance of the Medulla during postnatal stages. We also investigate the varying roles that receptors belonging to the tumor necrosis factor receptor superfamily have on thymus Medulla development and formation, and highlight the impact that T-cell development has on thymus Medulla formation. Finally, we examine the evidence that the Thymic Medulla plays an important role during the intraThymic generation of distinct αβT-cell subtypes. Collectively, these studies provide new insight into the development and functional importance of Medullary microenvironments during self-tolerant T-cell production in the thymus.
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differential requirement for ccr4 and ccr7 during the development of innate and adaptive αβt cells in the adult thymus
Journal of Immunology, 2014Co-Authors: Jennifer E Cowan, Arnauld Sergé, Magali Irla, Sonia M Parnell, Peter J L Lane, Eric J Jenkinson, Nicholas I Mccarthy, Andrea J White, Andrea Bacon, William E JenkinsonAbstract:αβT cell development depends upon serial migration of thymocyte precursors through cortical and Medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional αβT cells are subject to clonal deletion in the Medulla, entry into the thymus Medulla also fosters αβT cell differentiation. For example, during postnatal periods, the Medulla is involved in the intraThymic generation of multiple αβT cell lineages, notably the induction of Foxp3+ regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional αβT cells to the Medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to Medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple αβT cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire−/− mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the Thymic Medulla and influences the balance of early and late intraThymic stages of Foxp3+ regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intraThymic T cell development, highlighting its importance in enabling multiple αβT cell lineages to access the Thymic Medulla.
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the Thymic Medulla is required for foxp3 regulatory but not conventional cd4 thymocyte development
Journal of Experimental Medicine, 2013Co-Authors: Jennifer E Cowan, Sonia M Parnell, Kyoko Nakamura, Jorge Caamano, Peter J L Lane, Eric J Jenkinson, William E Jenkinson, Graham AndersonAbstract:A key role of the Thymic Medulla is to negatively select autoreactive CD4+ and CD8+ thymocytes, a process important for T cell tolerance induction. However, the involvement of the Thymic Medulla in other aspects of αβ T cell development, including the generation of Foxp3+ natural regulatory T cells (nTreg cells) and the continued maturation of positively selected conventional αβ T cells, is unclear. We show that newly generated conventional CD69+Qa2− CD4 single-positive thymocytes mature to the late CD69−Qa2+ stage in the absence of RelB-dependent Medullary Thymic epithelial cells (mTECs). Furthermore, an increasing ability to continue maturation extraThymically is observed within the CD69+CCR7−/loCCR9+ subset of conventional SP4 thymocytes, providing evidence for an independence from Medullary support by the earliest stages after positive selection. In contrast, Foxp3+ nTreg cell development is Medullary dependent, with mTECs fostering the generation of Foxp3−CD25+ nTreg cell precursors at the CD69+CCR7+CCR9− stage. Our results demonstrate a differential requirement for the Thymic Medulla in relation to CD4 conventional and Foxp3+ thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3+ nTreg cell development through the generation of Foxp3−CD25+ nTreg cell precursors.
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Aire is not Required for Vγ5+ DETC Progenitor Clustering with mTEC.
2013Co-Authors: Kyoko Nakamura, Sonia M Parnell, Eric J Jenkinson, William E Jenkinson, Andrea J White, Peter J. Lane, Graham AndersonAbstract:(A) Representative confocal analysis of E18 WT and Aire−/− thymus sections. Vγ5+ cells are shown in green, CD8β+ cells are shown in red and EpCAM+ Medullary areas are shown in blue. M denotes Medulla, C denotes cortex. Scale bars in A represent 100 µm. (B) Quantification of Vγ5+ cells per mm2 Thymic Medulla. WT; n = 6, Aire−/−; n = 6. Error bars represents SEM. (C) Individual thymus lobes of E18 WT and Aire−/− embryos were teased apart and stained for Vγ5, CD3, CD24 and CD45RB expression. Numbers shown on FACS plot are the mean percentages +/− SD. WT; n = 9, Aire−/−; n = 4.
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rank signaling links the development of invariant γδ t cell progenitors and aire Medullary epithelium
Immunity, 2012Co-Authors: Natalie A Roberts, Kyoko Nakamura, William E Jenkinson, Andrea J White, Fiona M Mcconnell, Gleb Turchinovich, David R Withers, Guillaume Desanti, Cecile BenezechAbstract:The Thymic Medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing Medullary Thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus Medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation.