Neoplastic thymic epithelial cells of human thymoma support T cell development from CD4−CD8− cells to CD4+CD8+ cellsin vitro

Abstract

Human thymoma is a thymic epithelial cell tumour which often contains a large number of immature T cells and is frequently associated with autoimmune diseases. Since thymic epithelial cells play key roles in the development and selection of T cells in the normal thymus, we hypothesized that the neoplastic thymic epithelial cells of thymoma may support T cell differentiation in the tumour. We characterized CD4-CD8- cells in thymoma and applied an in vitro reconstitution culture system using the CD4-CD8- cells and the neoplastic epithelial cells isolated from thymoma. CD34, a stem cell marker, was expressed on 29.9 +/- 12.2% of CD4-CD8- cells in thymoma. TCRgammadelta was expressed on 27.4 +/- 15.1% of CD4-CD8- cells and CD19, a B cell marker, was expressed on 14.1 +/- 23.1% of CD4-CD8- cells. CD4-CD8- cells expressed both IL-7R alpha-chain and common gamma-chain. Purified CD4-CD8- cells from thymomas were cultured with the neoplastic epithelial cells, and their differentiation into CD4+CD8+ cells via CD4 single-positive intermediates was observed within 9 days' co-culture in the presence of recombinant IL-7. Furthermore, we examined the reconstitution culture using CD34+CD4-CD8- cells purified from normal infant thymus. The CD34+CD4-CD8- cells in normal thymus also differentiated to CD4+CD8+ cells in the allogeneic co-culture with the neoplastic epithelial cells of thymoma. These results indicate that the tumour cells of thymoma retain the function of thymic epithelial cells and can induce differentiation of T cells in thymoma.

Immunological function of thymoma and pathogenesis of paraneoplastic myasthenia gravis

“…In fact, a study that utilized an in vitro culture system showed that neoplastic epithelial cells from thymomas induced differentiation of CD4 − CD8 − T-cell precursors to CD4 + CD8 + double-positive T cells. 19 Several types of malignant lymphomas also have the CD4 + CD8 + double-positive phenotype, although those lymphoma neoplastic cells are quite different from CD4 + CD8 + double-positive T cells found in thymomas. Lymphoma neoplastic cells with the CD4 + CD8 + phenotype have a certain level of CD3 expression, indicating that neoplastic lymphoma cells emerged from a T cell at a particular stage of T-cell differentiation in the thymus.…”

Glucocorticoids induce G1 cell cycle arrest in human neoplastic thymic epithelial cells

“…Isolation of thymoma-derived neoplastic epithelial cells TECs were obtained from fresh thymomas, as previously described (Inoue et al 1998;Inoue et al 1999). Fresh tissue from the eight patients was minced and cultured for 5 days in the presence of 1.35 mM 2-deoxyguanosine (Sigma, St. Louis, Mo., USA) in complete medium (RPMI 1640 supplemented with 10% FCS, 2 mM glutamine, 5 lM 2-mercaptoethanol, and antibiotics) to remove thymocytes.…”

“…To determine the percentage of positively stained cells, the range was set as closely as possible so that 99% of the control stained cells fell within the negative region. The expression level of each molecule was also evaluated in terms of the D-value, as in the non-parametric Kolmogorov-Smirnov test, using Cell Quest (Inoue et al 1998;Kadota et al 2000;Young 1977). The results are shown as the mean percentage±SD.…”

Role of Positive Selection of Thymoma-Associated T Cells in the Pathogenesis of Myasthenia Gravis

“…Interestingly, a considerable portion of these thymomaassociated lymphocytes are CD4 ϩ CD8 ϩ double positive, a phenotype of the cortical thymocytes [5][6][7][8][9], suggesting that thymoma neoplastic epithelial cells retain function as the thymic epithelium to induce T cell development. Actually, the neoplastic epithelial cells derived from thymomas have been shown to be capable of inducing CD4 ϩ CD8 ϩ cells from CD3 -CD4 -CD8 -CD34 ϩ T cell precursors in an in vitro culture [10]. Additionally, another observation that CD4 ϩ CD8 ϩ double positive lymphocytes exist even in the thymoma metastatic sites [11] strongly suggests that T cell development takes place even in a thymoma neoplastic environment.…”