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Down-Regulation of p27^Kip1 Expression Is Required for Development and Function of T Cells¹

Tadasuke Tsukiyama^*,, Noriko Ishida^*,, Michiko Shirane^*,, Yohji A. Minamishima^*,, Shigetsugu Hatakeyama^*,, Masatoshi Kitagawa^*,, Keiko Nakayama^, and Kei-ichi Nakayama^2,*,,

^* Department of Molecular and Cellular Biology and Laboratory of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Fukuoka, Japan; and Core Research for Engineering, Science, and Technology, Kawaguchi, Japan

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.

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