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Systematic Comparison of Gene Expression between Murine Memory and Naive B Cells Demonstrates That Memory B Cells Have Unique Signaling Capabilities¹

Mary M. Tomayko^2,*, Shannon M. Anderson^3,, Catherine E. Brayton^*, Saheli Sadanand, Natalie C. Steinel^*, Timothy W. Behrens^4, and Mark J. Shlomchik^,

^* Department of Dermatology, Department of Immunobiology, and Department of Laboratory Medicine, School of Medicine, Yale University, New Haven, CT 06510; and Center for Immunology, Medical School, University of Minnesota, Minneapolis, MN 55455

Memory B cells play essential roles in the maintenance of long-term immunity and may be important in the pathogenesis of autoimmune disease, but how these cells are distinguished from their naive precursors is poorly understood. To address this, it would be important to understand how gene expression differs between memory and naive B cells to elucidate memory-specific functions. Using model systems that help overcome the lack of murine memory-specific markers and the low frequency of Ag-specific memory and naive cells, we undertook a global comparison of gene expression between memory B cells and their naive precursors. We identified genes with differential expression and confirmed the differential expression of many of these by quantitative RT-PCR and of some of these at the protein level. Our initial analysis revealed differential expression patterns of genes that regulate signaling. Memory B cells have increased expression of genes important in regulating adenosine signaling and in modulating cAMP responses. Furthermore, memory B cells up-regulate receptors that are essential for embryonic stem cell self-renewal. We further demonstrate that one of these, leukemia inhibitory factor receptor, can initiate functional signaling in memory B cells whereas it does not in naive B cells. Thus, memory and naive B cells are intrinsically wired to signal differently from one another and express a functional signaling pathway that is known to maintain stem cells in other lineages.

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 A143603. M.M.T. was supported by the Dermatology Foundation and the Arthritis Foundation.

² Address correspondence and reprint requests to Dr. Mary M. Tomayko, Department of Dermatology, School of Medicine, Yale University, Box 208059, New Haven, CT 06520-8059. E-mail address: mary.tomayko{at}yale.edu

³ Current address: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143.

⁴ Current address: Genentech, South San Francisco, CA 94080.

⁵ Abbreviations used in this paper: NP, nitrophenyl; qPCR, quantitative RT-PCR; Tg, transgenic; KO, knockout; CGG, chicken gammaglobulin; GC, germinal center; NIP, (4-hydroxy-5-iodo-3-nitrophenyl)acetyl; PI, propidium iodide; SA, streptavidin; Lifr, leukemia inhibitory factor receptor; PKC, protein kinase C; GPCR, G protein-coupled receptor; Rgs, regulator of G protein signaling; PKA, protein kinase A; AKAP, A-kinase anchoring protein.

⁶ The online version of this article contains supplemental material.