The protein kinase encoded by the Tpl2 protooncogene plays an obligatory role in the transduction of Toll-like receptor and death receptor signals in macrophages, B cells, mouse embryo fibroblasts, and epithelial cells in culture and promotes inflammatory responses in animals. To address its role in T cell activation, we crossed the T cell receptor (TCR) transgene 2C, which recognizes class I MHC presented peptides, into the Tpl2^−/− genetic background. Surprisingly, the TCR2C^tg/tg/Tpl2^−/− mice developed T cell lymphomas with a latency of 4–6 months. The tumor cells were consistently TCR2C⁺CD8⁺CD4⁻, suggesting that they were derived either from chronically stimulated mature T cells or from immature single positive (ISP) cells. Further studies showed that the population of CD8⁺ ISP cells was not expanded in the thymus of TCR2C^tg/tg/Tpl2^−/− mice, making the latter hypothesis unlikely. Mature peripheral T cells of Tpl2^−/− mice were defective in ERK activation and exhibited enhanced proliferation after TCR stimulation. The same cells were defective in the induction of CTLA4, a negative regulator of the T cell response, which is induced by TCR signals via ERK. These findings suggest that Tpl2 functions normally in a feedback loop that switches off the T cell response to TCR stimulation. As a result, Tpl2, a potent oncogene, functions as a tumor suppressor gene in chronically stimulated T cells.