Regulation of Th-POK and Runx3 in T cell development in human thymoma.
ABSTRACT Thymoma is a thymic epithelial neoplasm which induces T cell development. However, the frequency of mature CD4(+) T cells in thymomas is lower than in normal thymi. Recently, CD4/CD8 lineage commitment has been elucidated in animal model. The zinc finger transcription factor Th-POK is a critical factor to CD4(+) T cell development in CD4/CD8 lineage commitment, whereas CD8(+) T cell development requires the transcription factor Runx3. These factors antagonize in CD4/CD8 lineage commitment. In this study, we examined Th-POK and Runx3 mRNA expression in the T cell subsets of human normal thymus and thymoma. A quantitative reverse transcriptase-polymerase chain reaction examination revealed that Th-POK expression in normal thymi was higher in the CD4(+)CD8(-) subset than in the CD4(+)CD8(+) and CD4(-)CD8(+) subsets. In thymomas, Th-POK expression in the CD4(+)CD8(-) subset was significantly lower than that in normal thymi, and was significantly correlated with the proportion of CD3(+) cells in the CD4(+)CD8(-) subset. However, Th-POK expressions of the CD3(+)CD4(+)CD8(+) and CD3(+)CD4(+)CD8(-) subsets were not impaired in thymomas compared to normal thymi. These results suggest that thymoma neoplastic epithelial cells can induce Th-POK expression similarly to the normal thymic epithelial cells. In addition, there was no significant difference in Runx3 expression between normal thymi and thymomas. Therefore, CD4/CD8 lineage commitment dependent on Th-POK and Runx3 system seems to be working even in the neoplastic environment formed by human thymomas.
- [show abstract] [hide abstract]
ABSTRACT: Thymoma and thymic carcinoma are the representative tumors arising from the thymic epithelium. Thymoma is well known for association with autoimmune diseases including myasthenia gravis, suggesting its biological activity. Herein, recent progress in research of thymoma is reviewed with reference to its immunological function. Myasthenia gravis is frequently associated with WHO type B1 and B2 thymomas. These types of thymomas hold a significant number of CD4(+)CD8(+) double-positive T cells, and at the same time, the neoplastic epithelial cells express HLA-DR molecules at a slightly reduced level compared with the normal thymus. The impaired expression of HLA-DR molecules in neoplastic epithelial cells of thymomas possibly affects positive selection of CD4(+)CD8(-) single-positive T cells and may result in alteration of its repertoire. The function of thymoma neoplastic cells as the cortical epithelium of the thymus and the morphological resemblance of thymomas to the cortex suggest that thymoma is of cortical epithelial origin; this might imply that thymoma lacks the functional medulla where professional antigen-presenting cells are engaged in negative selection. These findings suggest that thymoma generates autoreactive T cells causing autoimmunity. Further investigation on immunological function of thymoma is supposed to elucidate the pathogenesis of thymoma-related autoimmunity and the high affinity of thymoma with myasthenia gravis. In addition, studying the biology of thymoma is also expected to contribute to further understanding of T-cell development and immunological tolerance in the human, because thymoma can be considered an acquired thymus.General Thoracic and Cardiovascular Surgery 05/2008; 56(4):143-50.
- Clinical Immunology and Immunopathology 02/1996; 78(1):1-5.
- [show abstract] [hide abstract]
ABSTRACT: We have used organ culture of fetal thymic lobes from T cell receptor (TCR) transgenic beta 2M(-/-) mice to study the role of peptides in positive selection. The TCR used was from a CD8+ T cell specific for ovalbumin 257-264 in the context of Kb. Several peptides with the ability to induce positive selection were identified. These peptide-selected thymocytes have the same phenotype as mature CD8+ T cells and can respond to antigen. Those peptides with the ability to induce positive selection were all variants of the antigenic peptide and were identified as TCR antagonist peptides for this receptor. One peptide tested, E1, induced positive selection on the beta 2M(-/-) background but negative selection on the beta 2M(+/-) background. These results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy ligands mediate positive selection.Cell 02/1994; 76(1):17-27. · 31.96 Impact Factor