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      Abnormal Thymic Microenvironment in Insulin-Like Growth Factor-II Transgenic Mice

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          Objectives: Intrathymic T cell differentiation is driven by the thymic microenvironment, a tridimensional network of cells and extracellular matrix (ECM). Previous data showed that lymphoid and microenvironmental compartments are under the control of hormones and growth factors. We then attempted to define if insulin-like growth factor-II (IGF-II) was also involved in such a control. Methods: We used IGF-II transgenic (Tg) mice and studied their thymic microenvironment by immunohistochemistry. Moreover, we evaluated thymocytes in terms of their ability to adhere to thymic epithelial cells and to migrate through epithelial cells and ECM. Results: Transgenic IGF-II expression results in abnormalities of the thymic epithelium. Terminal differentiation of thymic epithelial cells (TEC) is modified, with the appearance of large clusters of cells immunoreactive to the monoclonal antibody KL1, which specifically recognizes highly differentiated TEC. Accordingly, treatment of cultured TEC with exogenous IGF-II induces the appearance of KL1+ cells and increases TEC proliferation. IGF-II Tg animals exhibit increased serum levels of the TEC-derived hormone thymulin. These effects were seen even when the IGF-II transgene was inserted in dwarf mice. Moreover, deposition of fibronectin and laminin is also enhanced in IGF-II Tg mouse thymus and in IGF-II-treated TEC cultures. Furthermore, ECM-mediated interactions between thymocytes and TEC are affected by exogenous IGF-II, as exemplified by the enhancement of thymocyte adhesion to TEC monolayers and thymocyte migration in thymic nurse cell complexes. Conclusions: Our data indicate that IGF-II pleiotropically affects the thymic epithelium, both in vivo and in vitro, and that some of these changes may have consequences on thymocyte/TEC interactions.

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          Most cited references 16

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          Identification and characterization of thymic epithelial progenitor cells.

          T cell differentiation and repertoire selection depend critically on several distinct thymic epithelial cell types, whose lineage relationships are unclear. We have investigated these relationships via functional analysis of the epithelial populations within the thymic primordium. Here, we show that mAbs MTS20 and MTS24 identify a population of cells that, when purified and grafted ectopically, can differentiate into all known thymic epithelial cell types, attract lymphoid progenitors, and support CD4(+) and CD8(+) T cell development in nude mice. In contrast, other epithelial populations in the thymic primordium can fulfill none of these functions. These data establish that the MTS20(+)24(+) population is sufficient to generate a functional thymus in vivo and thus argue strongly that all thymic epithelial cell types derive from a common progenitor cell.
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            Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines?

            Cell migration is crucial for intrathymic T-cell differentiation. Chemokines and extracellular matrix proteins per se induce thymocyte migration, and recent data suggest a combinatorial role for these molecules in this event. For example, thymocyte migration induced by fibronectin plus CXCL12/SDF1-alpha (stromal cell-derived factor1-alpha) is higher than that elicited by the chemokine alone. If such interactions are relevant in the thymus, abnormal expression of any of these ligands and/or their corresponding receptors will lead to defects in thymocyte migration. At least in the murine model of Chagas disease, this seems to be the case. Therefore a better knowledge of this complex biological circuitry will provide new clues for understanding thymus physiology and designing therapeutic strategies targeting developing T cells.
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              Neuroendocrine Control of Thymus Physiology

               W Savino (2000)

                Author and article information

                S. Karger AG
                March 2005
                17 March 2005
                : 12
                : 2
                : 100-112
                aLaboratory on Thymus Research, Department of Immunology, and bDepartment of Ultrastructure and Cell Biology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; cCNRS UMR 8147 and Inserm U-344, University Paris V, Hôpital Necker, Paris, France; dMassachusetts General Hospital, Harvard Medical School, Boston, Mass., USA; eDepartment of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
                83582 Neuroimmunomodulation 2005;12:100–112
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 9, References: 26, Pages: 13
                Original Paper


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