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

Abstract

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 CD4þ and CD8 þ thymocytes in adult mice (39^10 £ 10 6 in transgenic mice and 12^5 £ 10 6 in age-matched controls). Furthermore, thymocyte export was disturbed.

Neoplastic transformation and angiogenesis in the thymus of transgenic mice expressing SV40 T and t antigen under an l‐pyruvate kinase promoter (SV12 mice)

“…The first point of discussion concerns the almost exclusive proliferation of the MTS10‐positive cells, corresponding to the epithelial cells present only in the medullary zone of the thymus. As reported previously (Nabarra et al . 2002) and in the present study, double labelling with specific antibodies showed that these medullary epithelial cells also express the transgene.…”

“…In the thymus of SV12 Tg mice, progressive stages of morphological modifications are observed with age. The early phases, comprising hyperplasia and the initiation of tumoral development (postnatal to around 2 months), have been previously described in relation with lymphocyte maturation (Nabarra et al . 2002).…”

“…This tumour appears in the SV12 mouse line, obtained by transgenesis of SV40 T and t antigens with l ‐pyruvate kinase as the enhancer/promoter. In numerous series and generations, all mice expressing the transgene consistently develop thymic tumours (Nabarra et al . 2002).…”

“…In a previous paper, we have described the first phases of modification of the microenvironment, which involve alterations in the number and phenotype of thymocytes. Indeed, the total number of thymocytes is increased, as well as the proportion of mature thymocytes and alterations of export function towards the periphery are detected (Nabarra et al . 2002).…”

Loss of Pten Disrupts the Thymic Epithelium and Alters Thymic Function

“…Masson’s trichrome provides an alternative way to define the medullary and cortical regions of the thymus [ 31 ]. With this stain, Keratins are marked in red, collagen stains blue, nuclei stain dark, and the cytoplasm of cells stains light red or pink.…”