Cytokine-stimulated T lymphocyte proliferation is regulated by p27Kip1

• Published in: The Journal of immunology (1950) 2000-12, Vol.165 (11), p.6270-6277
• Main Authors: Zhang, S, Lawless, V A, Kaplan, M H
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - deficiency; Adjuvants, Immunologic - genetics; Adjuvants, Immunologic - physiology; Animals; Antigens - administration & dosage; Antigens - immunology; CD3 Complex - immunology; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Cycle Proteins; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins - physiology; Cytokines - antagonists & inhibitors; Cytokines - physiology; Growth Inhibitors - physiology; Hemocyanins - administration & dosage; Hemocyanins - immunology; Immune Sera - pharmacology; Immunologic Memory - genetics; Immunologic Memory - immunology; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins - deficiency; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - physiology; Signal Transduction - genetics; Signal Transduction - immunology; STAT6 Transcription Factor; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Trans-Activators - deficiency; Trans-Activators - genetics; Tumor Suppressor Proteins
• ISSN: 0022-1767

T lymphocyte growth is regulated by the cyclin-dependent kinase inhibitor p27(Kip1). Mice deficient in p27(Kip1) have increased proliferative responses to multiple cytokines, including IL-2, IL-4, and IL-12, but not to anti-CD3. In the absence of p27(Kip1), T cells proliferate faster than control cells, as evidenced by increased [(3)H]thymidine uptake, increased cell growth and division, and an increased number of cells in S phase. Importantly, this regulation is specific for p27(Kip1) in T cells, because hyperproliferation of T cells from mice deficient in p21(Cip1/Waf1) was not observed. In vivo, there is an expansion of activated/memory CD4(+) cells in p27(Kip1)-deficient mice before and after immunization. Furthermore, Ag-stimulated spleen cells from immunized p27(Kip1)-deficient mice demonstrated increased proliferative responses to IL-2 and increased secretion of IFN-gamma. Although IL-4 stimulated proliferative responses are diminished in Stat6-deficient T cells, activated T cells from mice doubly deficient in both p27(Kip1) and Stat6 recover normal proliferative responses to IL-4. Together, these data firmly support a role for p27(Kip1) as a negative regulator of cytokine-stimulated T cell growth.