부산대학교 도서관

Background: Upon engagement of the T cell receptor for antigen, its associated CD3 proteins recruit signal transduction molecules, which in turn regulate T lymphocyte proliferation, apoptosis, and thymocyte development. Because some signal transducing molecules recruited by CD3-ε, i.e., p56lck and p59fyn, are oncogenic and since we previously found that overexpression of CD3-ε transgenes causes a block in T lymphocyte and NK cell development, we tested the hypothesis that aberrant CD3-ε signaling leads both to abnormal T lymphocyte death and lymphomagenesis.Materials and Methods: Ten independently derived transgenic mouse lines were generated with four different genomic CD3-ε constructs. Mice either homozygous or hemizygous for each transgene were analyzed for an arrest in T lymphocyte development and for the occurrence of T cell lymphomas.Results: Aggressive clonal T cell lymphomas developed at very high frequencies in seven mouse lines with intermediate levels of copies of CD3-ε derived transgenes. However, these lymphomas were not found when high copy numbers of CD3-ε transgenes caused a complete block in early thymic development or when a transgene was used in which the exons coding for the CD3-ε protein were deleted. Analyses of a series of double mutant mice, tgCD3-ε × RAG-2null, indicated that lymphomagenesis was initiated in lineage-committed prothymocytes, i.e., before rearrangement of the T cell receptor genes. In addition, the transgene coding for the CD3-ε cytoplasmic domain and its transmembrane region induced a T cell differentiation signal in premalignant tgCD3-ε× RAG-2null mice.Conclusion: The nonenzymatic CD3-ε protein acted as a potent oncogene when overexpressed early in T lymphocyte development. Lymphomagenesis was dependent on signal transduction events initiated by the cytoplasmic domain of CD3-ε.