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¹ Division of Hematology-Oncology, ² Abramson Family Cancer Research Institute, ³ Department of Pathology and Laboratory Medicine, and ⁴ Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104

CORRESPONDENCE Warren S. Pear: wpear{at}mail.med.upenn.edu

Genetic inactivation of Notch signaling in CD4^–CD8^– double-negative (DN) thymocytes was previously shown to impair T cell receptor (TCR) gene rearrangement and to cause a partial block in CD4⁺CD8⁺ double-positive (DP) thymocyte development in mice. In contrast, in vitro cultures suggested that Notch was absolutely required for the generation of DP thymocytes independent of pre-TCR expression and activity. To resolve the respective role of Notch and the pre-TCR, we inhibited Notch-mediated transcriptional activation in vivo with a green fluorescent protein–tagged dominant-negative Mastermind-like 1 (DNMAML) that allowed us to track single cells incapable of Notch signaling. DNMAML expression in DN cells led to decreased production of DP thymocytes but only to a modest decrease in intracellular TCRß expression. DNMAML attenuated the pre-TCR–associated increase in cell size and CD27 expression. TCRß or TCRß transgenes failed to rescue DNMAML-related defects. Intrathymic injections of DNMAML^– or DNMAML⁺ DN thymocytes revealed a complete DN/DP transition block, with production of DNMAML⁺ DP thymocytes only from cells undergoing late Notch inactivation. These findings indicate that the Notch requirement during the ß-selection checkpoint in vivo is absolute and independent of the pre-TCR, and it depends on transcriptional activation by Notch via the CSL/RBP-J–MAML complex.

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