The neuropeptides oxytocin (OT) and vasopressin (VP) are synthesized in the human thymus in a sim... more The neuropeptides oxytocin (OT) and vasopressin (VP) are synthesized in the human thymus in a similar way as in the hypothalamo-neurophypophyseal system. Immunocytochemistry with polyclonal and monoclonal antibodies revealed that immunoreactive OT- and VP-producing cells are localized in the subcapsular cortex and medulla of human and murine thymuses. The epithelial nature of the neuroendocrine thymic cells is demonstrated by their immunostaining with a monoclonal antibody against cytokeratin. An original example of a neuroendocrine-immune microenvironment is given by the thymic nurse cells which are composed of a large neuroendocrine epithelial cell enclosing numerous mitotic immature thymocytes. These observations and the previously reported mitogenic and immunomodulatory properties of VP and OT upon mature T cells and thymocytes strongly support the existence of a neuroendocrine thymo-lymphoid axis and an active role of thymic VP and OT in T cell differentiation and activation.
In this paper, different experimental arguments will be presented wich support an influence of in... more In this paper, different experimental arguments will be presented wich support an influence of intrathymic neuropeptides in T cell ontogeny
The thymus is the primary site of T-cell repertoire arousal and induction of tolerance to “self” ... more The thymus is the primary site of T-cell repertoire arousal and induction of tolerance to “self” molecules, as well as major histocompatibility complex (MHC)-restriction. Neonatal thymectomy or congenital absence of the thymus (as in the mutant nude mouse or in patients presenting Di George’s syndrome) induces a profound failure of T-cell development, while B-cell maturation and functions are intact. In humans, however, neonatal thymectomy does not produce massive T-cell depletion, because the thymus exerts its full properties during fetal development. Recently, the question of an extra-thymic T-cell differentiation also has been addressed. Before the characterization of its fundamental immunological properties, the thymus was considered an endocrine gland, and intensive research was conducted with the objective of isolating thymus hormones (1,2).
... J Exp Med, 1999, 190, 479-486. 8. Hazenberg MD, Otto SA, de Pauw ES, et al. T-cell receptor ... more ... J Exp Med, 1999, 190, 479-486. 8. Hazenberg MD, Otto SA, de Pauw ES, et al. T-cell receptor excision circle and T-cell dynamics after allo-geneic stem cell transplantation are related to clinical events. Blood, 2002, 99, 3449-3453. ...
The thymus, the lymphoid organ responsible for the induction of central T cell self-tolerance, is... more The thymus, the lymphoid organ responsible for the induction of central T cell self-tolerance, is the site of expression of peptides belonging to the neurohypophysial peptide family. The classical model of neurosecretion established by the Scharrers for the hypothalamo-neurohypophysial axis however cannot be applied to characterize the secretory pathways of neurohypophysial-related peptides in the thymic epithelial component. The novel model of cell-to-cell cryptocrine signalling has recently been proposed by J.W. Funder to describe the molecular relationships between fixed epithelial cells and migratory differentiating cells. In the thymus, the cryptocrine signalling is further closely associated to the presentation of the "self" molecular structure by major histocompatibility complex-derived proteins to developing T cells. On the basis of our observations, the model of the thymic repertoire of neuroendocrine "self" antigens transposes to the molecular peptide level the dual physiological role of the thymus in T cell negative and positive selection. Moreover, this model should also contribute to a better understanding of the molecular mechanisms underlying the central T cell tolerance of "self" neuroendocrine functions.
In type 1 diabetes (T1D), β cells are destroyed by self-reactive T-cells resulting in progressive... more In type 1 diabetes (T1D), β cells are destroyed by self-reactive T-cells resulting in progressive insulin deficiency. More and more studies show that T1D could be initiated/favored by viral infections and especially Coxsackievirus B4 (enterovirus family, CVB4) but the mechanism is still not clear (1). T-cells are produced in the thymus and selected by thymic epithelial cells (TEC) in order to tolerize selfantigens like insulin (2a). TEC express numerous self-antigens, including insulin, and and Insulin-like growth factor 2 (IGF-2) is the dominant thymic peptide of the insulin family (2a). As IGF-2 is structurally highly similar to insulin, IGF-2 expression in the thymus could increase the negative selection of insulin specific T-cell and thus play a protective role against T1D (2b). We have shown that CVB4 is able to infect the thymus (in vivo and 3D culture) including TEC (primary cells and cell line), and is able to decrease Igf2 (TEC cell line) (3) . We hypothesize that CVB4 coul...
ABSTRACTEpidemiological studies have evidenced a link between type 1 diabetes (T1D) and infection... more ABSTRACTEpidemiological studies have evidenced a link between type 1 diabetes (T1D) and infections by enteroviruses, especially with coxsackievirus B4 (CV-B4). CV-B4 is able to infect human and murine thymic epithelial cells (TECs) and, in a murine TEC line, we have shown that the diabetogenic strain CV-B4 E2 decreases transcription of insulin-like growth factor 2 gene (Igf2), coding for the self-peptide of the insulin family. Here we show that in CV-B4 infection of mice alters Igf2 transcripts isoforms in TECs, followed by a decrease of pro-IGF2 precursor in the thymus. CV-B4 infection of a murine TEC line decreases Igf2 P3 promoter activity by targeting the region −68 to −22 upstream of the transcription start site (TSS) whereas Igf2 transcripts stability is not affected, pointing towards a regulation of Igf2 transcription. Our data also show that CV-B4 decreases IL-6/STAT3 signaling in vitro. This study provides new knowledge about the regulation of intrathymic Igf2 transcription...
The neuropeptides oxytocin (OT) and vasopressin (VP) are synthesized in the human thymus in a sim... more The neuropeptides oxytocin (OT) and vasopressin (VP) are synthesized in the human thymus in a similar way as in the hypothalamo-neurophypophyseal system. Immunocytochemistry with polyclonal and monoclonal antibodies revealed that immunoreactive OT- and VP-producing cells are localized in the subcapsular cortex and medulla of human and murine thymuses. The epithelial nature of the neuroendocrine thymic cells is demonstrated by their immunostaining with a monoclonal antibody against cytokeratin. An original example of a neuroendocrine-immune microenvironment is given by the thymic nurse cells which are composed of a large neuroendocrine epithelial cell enclosing numerous mitotic immature thymocytes. These observations and the previously reported mitogenic and immunomodulatory properties of VP and OT upon mature T cells and thymocytes strongly support the existence of a neuroendocrine thymo-lymphoid axis and an active role of thymic VP and OT in T cell differentiation and activation.
In this paper, different experimental arguments will be presented wich support an influence of in... more In this paper, different experimental arguments will be presented wich support an influence of intrathymic neuropeptides in T cell ontogeny
The thymus is the primary site of T-cell repertoire arousal and induction of tolerance to “self” ... more The thymus is the primary site of T-cell repertoire arousal and induction of tolerance to “self” molecules, as well as major histocompatibility complex (MHC)-restriction. Neonatal thymectomy or congenital absence of the thymus (as in the mutant nude mouse or in patients presenting Di George’s syndrome) induces a profound failure of T-cell development, while B-cell maturation and functions are intact. In humans, however, neonatal thymectomy does not produce massive T-cell depletion, because the thymus exerts its full properties during fetal development. Recently, the question of an extra-thymic T-cell differentiation also has been addressed. Before the characterization of its fundamental immunological properties, the thymus was considered an endocrine gland, and intensive research was conducted with the objective of isolating thymus hormones (1,2).
... J Exp Med, 1999, 190, 479-486. 8. Hazenberg MD, Otto SA, de Pauw ES, et al. T-cell receptor ... more ... J Exp Med, 1999, 190, 479-486. 8. Hazenberg MD, Otto SA, de Pauw ES, et al. T-cell receptor excision circle and T-cell dynamics after allo-geneic stem cell transplantation are related to clinical events. Blood, 2002, 99, 3449-3453. ...
The thymus, the lymphoid organ responsible for the induction of central T cell self-tolerance, is... more The thymus, the lymphoid organ responsible for the induction of central T cell self-tolerance, is the site of expression of peptides belonging to the neurohypophysial peptide family. The classical model of neurosecretion established by the Scharrers for the hypothalamo-neurohypophysial axis however cannot be applied to characterize the secretory pathways of neurohypophysial-related peptides in the thymic epithelial component. The novel model of cell-to-cell cryptocrine signalling has recently been proposed by J.W. Funder to describe the molecular relationships between fixed epithelial cells and migratory differentiating cells. In the thymus, the cryptocrine signalling is further closely associated to the presentation of the "self" molecular structure by major histocompatibility complex-derived proteins to developing T cells. On the basis of our observations, the model of the thymic repertoire of neuroendocrine "self" antigens transposes to the molecular peptide level the dual physiological role of the thymus in T cell negative and positive selection. Moreover, this model should also contribute to a better understanding of the molecular mechanisms underlying the central T cell tolerance of "self" neuroendocrine functions.
In type 1 diabetes (T1D), β cells are destroyed by self-reactive T-cells resulting in progressive... more In type 1 diabetes (T1D), β cells are destroyed by self-reactive T-cells resulting in progressive insulin deficiency. More and more studies show that T1D could be initiated/favored by viral infections and especially Coxsackievirus B4 (enterovirus family, CVB4) but the mechanism is still not clear (1). T-cells are produced in the thymus and selected by thymic epithelial cells (TEC) in order to tolerize selfantigens like insulin (2a). TEC express numerous self-antigens, including insulin, and and Insulin-like growth factor 2 (IGF-2) is the dominant thymic peptide of the insulin family (2a). As IGF-2 is structurally highly similar to insulin, IGF-2 expression in the thymus could increase the negative selection of insulin specific T-cell and thus play a protective role against T1D (2b). We have shown that CVB4 is able to infect the thymus (in vivo and 3D culture) including TEC (primary cells and cell line), and is able to decrease Igf2 (TEC cell line) (3) . We hypothesize that CVB4 coul...
ABSTRACTEpidemiological studies have evidenced a link between type 1 diabetes (T1D) and infection... more ABSTRACTEpidemiological studies have evidenced a link between type 1 diabetes (T1D) and infections by enteroviruses, especially with coxsackievirus B4 (CV-B4). CV-B4 is able to infect human and murine thymic epithelial cells (TECs) and, in a murine TEC line, we have shown that the diabetogenic strain CV-B4 E2 decreases transcription of insulin-like growth factor 2 gene (Igf2), coding for the self-peptide of the insulin family. Here we show that in CV-B4 infection of mice alters Igf2 transcripts isoforms in TECs, followed by a decrease of pro-IGF2 precursor in the thymus. CV-B4 infection of a murine TEC line decreases Igf2 P3 promoter activity by targeting the region −68 to −22 upstream of the transcription start site (TSS) whereas Igf2 transcripts stability is not affected, pointing towards a regulation of Igf2 transcription. Our data also show that CV-B4 decreases IL-6/STAT3 signaling in vitro. This study provides new knowledge about the regulation of intrathymic Igf2 transcription...
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