Transgenic expression of the p16(INK4a) cyclin-dependent kinase inhibitor leads to enhanced apoptosis and differentiation arrest of CD4-CD8- immature thymocytes.
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 gammadelta 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-CD3epsilon 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.
Lagresle
Chantal
C
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, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France.
Gardie
Betty
B
Eyquem
Stéphanie
S
Fasseu
Magali
M
Vieville
Jean-Claude
JC
Pla
Marika
M
Sigaux
François
F
Bories
Jean-Christophe
JC
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D012313:RNA / Q000032:analysis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
D000906:Antibodies; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; C064655:V(D)J recombination activating protein 2; D012313:RNA