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Schnurri-2 Controls Memory Th1 and Th2 Cell Numbers In Vivo¹

Motoko Y. Kimura^*, Chiaki Iwamura^*, Akane Suzuki^*, Takako Miki^*, Akihiro Hasegawa^*, Kaoru Sugaya^*, Masakatsu Yamashita^*, Shunsuke Ishii and Toshinori Nakayama^2,*

^* Department of Immunology, Graduate School of Medicine, Chiba University, Chiba; and Laboratory of Molecular Genetics, Institute of Physical and Chemical Research (Japan) Tsukuba Institute, Tsukuba, Ibaraki, Japan

Schnurri-2 (Shn-2) is a large zinc-finger containing protein, and it plays a critical role in cell growth, signal transduction and lymphocyte development. In Shn-2-deficient CD4 T cells, the activation of NF-B was up-regulated and their ability to differentiate into Th2 cells was enhanced. We herein demonstrate that Th1 and Th2 memory cells are not properly generated from Shn-2-deficient effector Th1/Th2 cells. Even a week after the transfer of effector Th1/Th2 cells into syngeneic mice, a dramatic decrease in the number of Shn-2-deficient donor T cells was detected particularly in the lymphoid organs. The transferred Shn-2-deficient Th1/Th2 cells express higher levels of the activation marker CD69. No significant defect in the BrdU incorporation in the Shn-2-deficient transferred CD4 T cells was observed. The numbers of apoptotic cells were selectively higher in Shn-2-deficient donor Th1/Th2 cell population. Moreover, Shn-2-deficient effector Th1 and Th2 cells showed an increased susceptibility to cell death in in vitro cultures with increased expression of FasL. Transfer of Th2 effector cells over-expressing the p65 subunit of NF-B resulted in a decreased number of p65-expressing cells in the lymphoid organs. As expected, T cell-dependent Ab responses after in vivo immunization of Shn-2-deficient mice were significantly reduced. Thus, Shn-2 appears to control the generation of memory Th1/Th2 cells through a change in their susceptibility to cell death.

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 was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (Japan) (Grants-in-Aid for Scientific Research in Priority Areas 17016010 and 17047007; Scientific Research B 17390139; Scientific Research C 18590466; Grant-in-Aid for Young Scientists 17790317 and 17790318; and Special Coordination Funds for Promoting Science and Technology); the Ministry of Health, Labor and Welfare (Japan); The Japan Health Science Foundation; Kanae Foundation; Uehara Memorial Foundation; Mochida Foundation; Yasuda Medical Foundation; Astellas Foundation; and Sagawa Foundation.

² Address correspondence and reprint requests to Dr. Toshinori Nakayama, Department of Immunology (H3), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Japan. E-mail address: tnakayama{at}faculty.chiba-u.jp

³ Abbreviations used in this paper: AICD, activation-induced cell death; T_CM, central memory T; T_EM, effector memory T; MIF, mean fluorescence intensity units; Shn-2, Schnurri-2; Shn-2^–/–, Shn-2-deficient; Tg, transgenic; PI, propidium iodide.