Down-Regulation of p27Kip1 Expression Is Required for Development and Function of T Cells

• Published in: The Journal of immunology (1950) Vol. 166; no. 1; pp. 304 - 312
• Main Authors: Tsukiyama, Tadasuke, Ishida, Noriko, Shirane, Michiko, Minamishima, Yohji A, Hatakeyama, Shigetsugu, Kitagawa, Masatoshi, Nakayama, Keiko, Nakayama, Kei-ichi
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01-01-2001
• Subjects: Animals; Cell Cycle Proteins; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Division - genetics; Cell Division - immunology; Crosses, Genetic; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases - antagonists & inhibitors; Down-Regulation - genetics; Down-Regulation - immunology; Female; Lymph Nodes - immunology; Lymph Nodes - pathology; Lymphocyte Activation - genetics; Lymphocyte Count; Lymphopenia - genetics; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Microtubule-Associated Proteins - antagonists & inhibitors; Microtubule-Associated Proteins - biosynthesis; Microtubule-Associated Proteins - genetics; Spleen - immunology; Spleen - pathology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Thymus Gland - immunology; Thymus Gland - metabolism; Thymus Gland - pathology; Tumor Suppressor Proteins
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.1.304

The proliferation of T cells is regulated in a development-dependent manner, but it has been unclear whether proliferation is essential for T cell differentiation. The cyclin-dependent kinase inhibitor p27(Kip1) is abundant throughout development in cells of the T cell lineage, with the exception of late stage CD4(-)CD8(-) thymocytes and activated mature T cells, both of which show a high rate of proliferation. The role of down-regulation of p27(Kip1) expression in T cell development and function has now been investigated by the generation and characterization of three strains of p27 transgenic mice that express the transgene at various levels specifically in the T cell lineage. The numbers of thymocytes at CD4(+)CD8(+), CD4(+)CD8(-), and CD4(-)CD8(+) stages of development as well as those of mature T cells in peripheral lymphoid tissues were reduced in transgenic mice in a manner dependent on the level of p27(Kip1) expression. The development of thymocytes in the transgenic strain in which p27(Kip1) is most abundant (p27-Tg(high) mice) appeared to be blocked at the CD4(-)CD8(-)CD25(+)CD44(low) stage. Peripheral T cells from p27-Tg(high) mice exhibited a reduced ability to proliferate in response to mitogenic stimulation compared with wild-type T cells. Moreover, Ag-induced formation of germinal centers and Ig production were defective in p27-Tg(high) mice. These results suggest that down-regulation of p27(Kip1) expression is required for the development, proliferation, and immunoresponsiveness of T cells.