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The Loss of PTEN Allows TCR ß Lineage Thymocytes to Bypass IL-7 and Pre-TCR–mediated Signaling

¹ Department of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
² Department of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
³ Department of Molecular Genetics, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
⁴ Department of Cell Biology and Histology, University of Amsterdam, Academic Medical Center, 1105 AZ Amsterdam, Netherlands
⁵ Institut National de la Sante et de la Recherche Medicale UMR 599, Institut de Recherches sur le Cancer de Marseille, 13009 Marseille, France
⁶ Department of Pathology, Erasmus Medical Centre, 3000 DR Rotterdam, Netherlands

Address correspondence to Hergen Spits, Dept. of Cell Biology and Histology, University of Amsterdam, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam. Phone: 31-20-5664977; Fax: 31-20-6974156; email: hergen.spits{at}amc.uva.nl

The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates cell survival and proliferation mediated by phosphoinositol 3 kinases. We have explored the role of the phosphoinositol(3,4,5)P3-phosphatase PTEN in T cell development by analyzing mice with a T cell–specific deletion of PTEN. Pten^flox/floxLck-Cre mice developed thymic lymphomas, but before the onset of tumors, they showed normal thymic cellularity. To reveal a regulatory role of PTEN in proliferation of developing T cells we have crossed PTEN-deficient mice with mice deficient for interleukin (IL)-7 receptor and pre–T cell receptor (TCR) signaling. Analysis of mice deficient for Pten and CD3; Pten and c; or Pten, c, and Rag2 revealed that deletion of PTEN can substitute for both IL-7 and pre-TCR signals. These double- and triple-deficient mice all develop normal levels of CD4CD8 double negative and double positive thymocytes. These data indicate that PTEN is an important regulator of proliferation of developing T cells in the thymus.

Key Words: PI-3K • thymus • Cre-LoxP • IL-7 receptor • pre–T cell receptor

Abbreviations used in this paper: DN, double negative; DP, double positive; ISP, immature single positive; Itk, IL-2–inducible T cell kinase; PDK-1, phosphoinositide-dependent kinase-1; PI-3K, phosphatidylinositol 3 kinase; PKB, protein kinase B; PTEN, phosphatase and tensin homologue deleted on chromosome 10; SP, single positive.

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