Early Steps of a Thymic Tumor in SV40 Transgenic Mice: Hyperplasia of Medullary Epithelial Cells and Increased Mature Thymocyte Numbers Disturb Thymic Export

Journal of Immunology Research, Sep 2018

Bone marrow progenitors migrate to the thymus, where they proliferate and differentiate into immunologically competent T cells. In this report we show that mice transgenic for SV40 T and t antigens under the control of the L-pyruvate kinase promoter develop, in a first step, thymic hyperplasia of both thymocytes and epithelial cells. Morphological studies (histology, immunohistolabeling and electron microscopy) revealed modifications of the thymic microenvironment and gradual expansion of medullary epithelial cells in 1 month-old mice, taking over the cortical region. Then, a thymic carcinoma develops. Two-color labeling of frozen sections identified the transgene in medullary epithelial cells. Flow cytometry analysis demonstrated a marked increase in mature CD4+ and CD8+ thymocytes in adult mice (39±10×106 in transgenic mice and 12±5×106 in age-matched controls). Furthermore, thymocyte export was disturbed.

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Early Steps of a Thymic Tumor in SV40 Transgenic Mice: Hyperplasia of Medullary Epithelial Cells and Increased Mature Thymocyte Numbers Disturb Thymic Export

Developmental Immunology, December 1044-6672 Early Steps of a Thymic Tumor in SV40 Transgenic Mice: Hyperplasia of Medullary Epithelial Cells and Increased Mature Thymocyte Numbers Disturb Thymic Export* BERNADETTE NABARRA 0 4 CATHERINE MARTINON 1 4 CE? CILE GODARD 0 4 FLORENCE VASSEUR 0 4 GEOFFROY DE RIBAINS 3 4 LUCILE MIQUEROL 3 4 AXEL KAHN 3 4 SOPHIE EZINE 0 4 0 INSERM U.345, Institut Necker , 75730, Paris Cedex 15 , France 1 INSERM U.238, CEA , 38054, Grenoble Cedex 9 , France 2 ; DP , double positive CD4 3 INSERM U. 129, CHU Cochin-Port-Royal, 75014, Paris , France 4 Abbreviations: DN , double negative CD4 Bone marrow progenitors migrate to the thymus, where they proliferate and differentiate into immunologically competent T cells. In this report we show that mice transgenic for SV40 T and t antigens under the control of the L-pyruvate kinase promoter develop, in a first step, thymic hyperplasia of both thymocytes and epithelial cells. Morphological studies (histology, immunohistolabeling and electron microscopy) revealed modifications of the thymic microenvironment and gradual expansion of medullary epithelial cells in 1 month-old mice, taking over the cortical region. Then, a thymic carcinoma develops. Two-color labeling of frozen sections identified the transgene in medullary epithelial cells. Flow cytometry analysis demonstrated a marked increase in mature CD4? and CD8? thymocytes in adult mice (39 ^ 10 ? 106 in transgenic mice and 12 ^ 5 ? 106 in age-matched controls). Furthermore, thymocyte export was disturbed. Immunohistolabeling; Ultrastructure; Thymic medullary tumor; L-pyruvate kinase promoter INTRODUCTION In the thymic microenvironment, the epithelial compartment is organized into cortical and medullary zones that mediate different aspects of thymocyte differentiation. The different processes controlling the growth and organization of the epithelial compartment depend largely on cell interactions involving thymocytes and stromal cells for selection, differentiation and maturation of T cells (Duijvestin et al., 1981; Weissman et al., 1982; Kendall, 1986; Nabarra, 1987; 1991a; Marrack, 1988; von Bohmer, 1988; Sprent et al., 1988; Brekelmans and van Ewijk, 1990; van Ewijk, 1991; Boyd et al., 1993) . Furthermore, thymic stroma cells included also nonepithelial cells (bone marrow-derived cells) as macrophages and interdigitated cells (IDC) which are also involved in these process. In this milieu, thymocytes are in symbiotic developmental relationship involving the different stromal cells and various signaling molecules, cytokines, cytokine receptors and chemokines (Zlotnik and Moore, 1995; Norment and Bevan, 2000) . T cell precursors migrating from the bone-marrow to the thymus undergo an ordered differentiation process. After different migrations steps across the organ, mature T cells are generated and exit the thymus for the periphery (Scollay et al., 1980; Pe?nit, 1986) . Migration and homing are partly dependent on adhesion molecules (Imhof et al., 1991; Aurrand-Lions et al., 1996) . Virtually nothing is known about the precise thymic location from which mature thymocytes emigrate from the thymus to peripheral lymphoid organs. However, the cortico-medullary junction has been suggested important in this process in association with maintenance of a normal architecture. The studies of all these parameters, particularly elucidation of the cross-talk between thymocytes and epithelial cells (van Ewijk et al., 1994; Pe?nit et al., 1996) , is difficult to appreciate in steady state conditions. Nevertheless, the studies of modification and disruption of the thymic microenvironment organization in different pathologic mice, and recently of genetically engineered mice, appeared to be a good approach in relation with observations of cellular modifications, alterations in the developmental program and phenotype of thymocytes (Rouse and Weissman, 1981; Kendall, 1986; Nabarra and Dardenne, 1991b; Naquet et al., 1999) . In this way, both naturally occurring and experimentally-induced tumors were used as models for dissecting in vivo these different sequences of T cell education, and disruption of thymic stroma. Transgenic model of pure thymic tumor is rarely described. Today only one team has described a thymic carcinoma issued of an extanded thymic hyperplasia in Tg mice made with SV40 Simian Virus T antigen 40 (SV40) associated with it own promoter (Park et al., 1996; Lee et al., 1998) . We have generated a second mouse model with SV40 T and t Ag with a different promoter (L-pyruvate kinase). SV12 transgenic mice develop early in life a massive thymic hyperplasia concerning both thymocytes and epithelial cells. Immuno-histological studies, confirmed by electron microscopy studies, demonstrate a large hyperplasia of expanded medullary epithelial cells, carrying the transgene. With time, large angiogenesis, numerous cellular atypies concerning the cytoplasm and the nucleus and a larg (...truncated)


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Bernadette Nabarra, Catherine Martinon, Cécile Godard, Florence Vasseur, Geoffroy de Ribains, Lucile Miquerol, Axel Kahn, Sophie Ezine. Early Steps of a Thymic Tumor in SV40 Transgenic Mice: Hyperplasia of Medullary Epithelial Cells and Increased Mature Thymocyte Numbers Disturb Thymic Export, Journal of Immunology Research, 9, DOI: 10.1080/10446670310001593532