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Transgenic Expression of the p16^INK4a Cyclin-Dependent Kinase Inhibitor Leads to Enhanced Apoptosis and Differentiation Arrest of CD4^-CD8^- Immature Thymocytes

Institut National de la Santé et de la Recherche Médicale, Unité 462, Laboratoire ^* 10, Ligue Nationale Contre le Cancer, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France

In the thymus, T cell development proceeds by successive steps of differentiation, expansion, and selection. Control of thymocyte proliferation is critical to insure the full function of the immune system and to prevent T cells from transformation. Deletion of the cell cycle inhibitor p16^INK4a is frequently observed in human T cell neoplasias and, in mice, gene targeted inactivation of the Ink4a locus enhances thymocyte expansion and predisposes mutant animal to tumorigenesis. Here, we investigate the mechanism by which p16^Ink4a controls thymocyte development by analyzing transgenic mice expressing the human p16^INK4a into the T cell lineage. We show that forced expression of p16^INK4a in thymocytes blocked T cell differentiation at the early CD4^-CD8^-CD3^-CD25⁺ stage without significantly affecting the development of T cells. Pre-TCR function was mimicked by the induction of CD3 signaling in thymocytes of recombinase activating gene (RAG)-2-deficient mice (RAG-2^-/-). Upon anti-CD3 treatment in vivo, p16^INK4a-expressing RAG-2^-/- thymocytes were not rescued from apoptosis, nor could they differentiate. Our data demonstrate that expression of p16^INK4a prevents the pre-TCR-mediated expansion and/or survival of differentiating thymocytes.

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