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Transgenic Mice Expressing Dominant-Negative Bright Exhibit Defects in B1 B Cells¹

Jamee C. Nixon^*, Scott Ferrell^*,, Cathrine Miner^*, Athenia L. Oldham^*,, Ute Hochgeschwender^*, and Carol F. Webb^2,*,,

^* Oklahoma Medical Research Foundation, Oklahoma City, OK 73104; and Department of Microbiology and Immunology and Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104

The transcription factor Bright up-regulates Ig H chain production from select V region promoters and requires Bright dimerization, Bruton’s tyrosine kinase (Btk), and the Btk substrate, TFII-I, for this activity. Defects in Btk cause X-linked immunodeficiency disease in mice and humans. Btk-deficient mice exhibit decreased serum IgM production, B cell developmental blocks, absence of peritoneal B1 cells, and subnormal immune responses against Ags, including phosphorylcholine, which confer protection against Streptococcus pneumoniae. Transgenic mice expressing dominant-negative Bright share similarities with Btk-deficient mice, including decreased serum IgM, poor anti-phosphorylcholine responses, and slightly reduced numbers of mature B cells. Although dominant-negative Bright mice developed B1 B cells, these were functionally deficient in Ig secretion. These data suggest a mechanistic explanation for the abnormal responses to phosphorylcholine observed in Btk-deficient mice, and indicate that Bright functions in a subset of Btk-dependent pathways in vivo, particularly those responses dominated by B1 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 by National Institutes of Health Grant AI44215.

² Address correspondence and reprint requests to Dr. Carol F. Webb, 825 N. E. 13th St., Oklahoma City, OK 73104. E-mail address: webbc{at}omrf.org

³ Abbreviations used in this paper: ARID, A + T-rich interacting domain; Btk, Bruton’s tyrosine kinase; DN, dominant negative; FOL, follicular mature; KLH, keyhole limpet hemocyanin; MZ, marginal zone; NP, nitrophenyl; PC, phosphorylcholine; TG, transgenic; WT, wild type.