Abstract
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.
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Acknowledgments
We thank Key Higgins for technical assistance, and Drs. Clyde Dawe, Tom Benjamin and Geoffrey Cooper for a critical review of the manuscript. This work was supported by a grant from the National Institutes of Health (PO1-AI 35714).
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Wang, B., She, J., Salio, M. et al. CD3-ε Overexpressed in Prothymocytes Acts as an Oncogene. Mol Med 3, 72–81 (1997). https://doi.org/10.1007/BF03401669
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DOI: https://doi.org/10.1007/BF03401669