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Caspase 6 Regulates B Cell Activation and Differentiation into Plasma Cells¹

Chie Watanabe^*, Geraldine L. Shu, Timothy S. Zheng^2,, Richard A. Flavell and Edward A. Clark^3,*,

^* Department of Immunology and Department of Microbiology, University of Washington, Seattle, WA 98195; and Department of Immunobiology, Yale University of School of Medicine, New Haven, CT 06520

Caspase (Casp) family proteases regulate not only lymphocyte apoptosis but also lymphocyte activation and development. In this study, we show that Casp6 regulates B cell activation and differentiation into plasma cells by modifying cell cycle entry. B cells from Casp6 knockout (Casp6 KO) mice examined ex vivo have more cells in G₁ than wild-type B cells, and mitogen-induced G₁ entry of Casp6 KO B cells is much faster than that of wild-type B cells. Even so, S phase entry and proliferation are not increased in Casp6 KO B cells. Rather than proliferating, activated Casp6 KO B cells preferentially differentiate into syndecan-1⁺ plasma cells and produce Abs. In Casp6 KO mice compared with WT mice, serum levels of IgG1, IgG2a, and IgG2b are increased and Ag-specific Ab responses are also enhanced along with increased percentages of syndecan-1⁺ plasma cells. Casp6 may regulate both B cell activation and differentiation by modifying requirements for G₀ B cells to enter G₁.

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 mainly by National Institutes of Health Grant GM37905 (to E.A.C.) and also by National Institutes of Health Grants DE16381 (E.A.C.) and RR00166 and by the Research Fellowship of Japan Society for the Promotion of Science (to C.W.).

² Current address: Immunobiology Biogen Idec, Inc., Cambridge, MA 02142.

³ Address correspondence and reprint requests to Dr. Edward A. Clark, Box 357330, 1959 NE Pacific Street, Seattle, WA 98195-7650. E-mail address: eclark{at}bart.rprc.washington.edu

⁴ Abbreviations used in this paper: Casp, caspase; KO, knockout; WT, wild type; PY, pyronin Y; CDK, cyclin-dependent kinase; Rb, retinoblastoma protein; TD, T cell dependent; VEID, benzyloxycarbonyl(Cbz)-Val-Glu-Ile-Asp(Ome)-fluoromethylketone; Ct, cycle threshold; 7AAD, 7-aminactinomycin D; GC, germinal center; IAP, inhibitor of apoptosis; pRb, phosphorylated Rb.