Mechanisms that limit the in vitro proliferative potential of human CD8+ T lymphocytes.
Human T lymphocytes can be numerically expanded in vitro only to a limited extent. The cyclin-dependent kinase inhibitor p16(INK4a) is essential in the control of cellular proliferation, and its expression, in epithelial cells, is associated with irreversible growth arrest. Using long-term cultured CD8+ T lymphocytes, we have investigated the role of the p16/pRb pathway in the regulation of T cell proliferation and senescence. In this study, we describe at least two mechanisms that cause replicative growth arrest in cultured lymphocytes. The first one depends on the expression of p16(INK4a) and is directly responsible for the exit of a significant proportion of CD8+ T cells from the proliferative population. This induced p16 expression pattern is observed during each round of mitogen stimulation and is not related to activation-induced cell death. Importantly, knocking down p16(INK4a) expression allows increased proliferation of T cells. The second one is a phenomenon that resembles human fibroblast senescence, but is independent of p16(INK4a) and of telomere attrition. Interestingly, virtually all pRb proteins in the senescent population are found in the active form. Our data indicate that newly synthesized p16(INK4a) limits the proliferation of T lymphocytes that respond to mitogen, but is not required for the loss of mitogen responsiveness called senescence.
Migliaccio
Marco
M
Swiss Institute for Experimental Cancer Research, National Center of Competence in Research Molecular Oncology, Epalinges, Switzerland.
Raj
Kenneth
K
Menzel
Olivier
O
Rufer
Nathalie
N
D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D019942:Genes, p16; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008934:Mitogens / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism; D016615:Telomere / Q000235:genetics
D019941:Cyclin-Dependent Kinase Inhibitor p16; D008934:Mitogens; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein