Open AccessTpl2 and ERK transduce antiproliferative T cell receptor signals and inhibit transformation of chronically stimulated T cells
Author(s) -
Christos Tsatsanis,
Katerina Vaporidi,
Vassiliki Zacharioudaki,
Ariadne Androulidaki,
Yuri Sykulev,
Andrew N. Margioris,
Philip N. Tsichlis
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0708381104
Subject(s) - microbiology and biotechnology , biology , cytotoxic t cell , t cell , t cell receptor , cd8 , mapk/erk pathway , signal transduction , immune system , immunology , biochemistry , in vitro
The protein kinase encoded by theTpl2 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 TCR2Ctg/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 TCR2Ctg/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.