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IL-7/STAT5 Cytokine Signaling Pathway Is Essential but Insufficient for Maintenance of Naive CD4 T Cell Survival in Peripheral Lymphoid Organs¹

Yoh-ichi Seki^*, Jianying Yang, Mariko Okamoto^*, Shinya Tanaka^*, Ryo Goitsuka, Michael A. Farrar and Masato Kubo^2,*

^* Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Kanagawa, Japan; Center for Immunology, The Cancer Center, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455; and Research Institute for Biological Sciences, Tokyo University of Science, Chiba, Japan

Constitutive expression of suppressors of cytokine signaling (SOCS)1 in T lineage in vivo attenuated cytokine signaling and resulted in a dramatic reduction in the number of naive CD44^lowCD62L^high CD4 T cells in the spleen. After adoptive transfer of thymocytes from SOCS1 transgenic mice into normal recipients, naive CD4 T cells rapidly disappeared from the spleen within 1 wk. Likewise, T cell-specific deletion of STAT5a/b in vivo resulted in a similar phenotype characterized by loss of naive CD4 T cells. Thus, STAT5-mediated signaling is crucial for promoting naive T cell survival. However, forced expression of constitutively active STAT5 failed to rescue CD4 T cells in SOCS1 transgenic mice, implying that STAT5 activation is necessary but not sufficient for naive CD4 T cell survival. Although blockade of the IL-7R, a SOCS1 target, resulted in clear inhibition of naive T cell survival, the effect occurred 3 wk after anti-IL-7R Ab treatment, but not at earlier time points. These results suggest that IL-7-mediated STAT5 activation is essential for long-term survival of naive CD4 cells after export from thymus, and that another SOCS1-sensitive cytokine is critical for short-term naive T cell survival.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by a Grant-in-Aid of Scientific Research in Priority Areas of the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M.K.), and by a Pew Scholar Award, a Cancer Research Investigator Award, and Grant AI50737 from the National Institutes of Health (to M.A.F.). Y.S. is supported by the Japan Society for the Promotion of Science.

² Address correspondence and reprint requests to Dr. Masato Kubo, Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Suehiro-cho 1-7-22, Tsurumi, Yokohama, Kanagawa 230-0045, Japan. E-mail address: raysolfc{at}rcai.riken.jp

³ Abbreviations used in this paper: _c, common -chain; SOCS, suppressors of cytokine signaling; CA, constitutively active; MP, memory phenotype; SP, single positive; Tg, transgenic.