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T Cell Leukemia/Lymphoma 1 and Galectin-1 Regulate Survival/Cell Death Pathways in Human Naive and IgM⁺ Memory B Cells through Altering Balances in Bcl-2 Family Proteins¹

Siamak Jabbarzadeh Tabrizi^*, Hiroaki Niiro^2,, Mariko Masui, Goichi Yoshimoto, Tadafumi Iino, Yoshikane Kikushige, Takahiro Wakasaki^¶, Eishi Baba, Shinji Shimoda, Toshihiro Miyamoto, Toshiro Hara^* and Koichi Akashi^,

^* Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka; Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, MA 02115; and ^¶ Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

BCR signaling plays a critical role in purging the self-reactive repertoire, or in rendering it anergic to establish self-tolerance in the periphery. Differences in self-reactivity between human naive and IgM⁺ memory B cells may reflect distinct mechanisms by which BCR signaling dictates their survival and death. Here we demonstrate that BCR stimulation protected naive B cells from apoptosis with induction of prosurvival Bcl-2 family proteins, Bcl-x_L and Mcl-1, whereas it rather accelerated apoptosis of IgM⁺ memory B cells by inducing proapoptotic BH3-only protein Bim. We found that BCR-mediated PI3K activation induced the expression of Mcl-1, whereas it inhibited Bim expression in B cells. Phosphorylation of Akt, a downstream molecule of PI3K, was more sustained in naive than IgM⁺ memory B cells. Abundant expression of T cell leukemia/lymphoma 1 (Tcl1), an Akt coactivator, was found in naive B cells, and enforced expression of Tcl1 induced a high level of Mcl-1 expression, resulting in prolonged B cell survival. In contrast, Galectin-1 (Gal-1) was abundantly expressed in IgM⁺ memory B cells, and inhibited Akt phosphorylation, leading to Bim up-regulation. Enforced expression of Gal-1 induced accelerated apoptosis in B cells. These results suggest that a unique set of molecules, Tcl1 and Gal-1, defines distinct BCR signaling cascades, dictating survival and death of human naive and IgM⁺ memory B cells.

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 in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (to S.J.T., H.N., T.H., and K.A.).

² Address correspondence and reprint requests to Dr. Hiroaki Niiro, Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail address: hniiro{at}med.kyushu-u.ac.jp

³ Abbreviations used in this paper: MZ, marginal zone; Gal-1, galectin-1; Tcl1, T cell leukemia/lymphoma 1; PLC, phospholipase C; h, human; EGFP, enhanced GFP; CLL, chronic lymphocytic leukemia; BAFF, B cell-activating factor of the TNF family.