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Reduced c-myc Expression Levels Limit Follicular Mature B Cell Cycling in Response to TLR Signals¹

Almut Meyer-Bahlburg^2,*, Ashok D. Bandaranayake, Sarah F. Andrews and David J. Rawlings^3,*,

^* Seattle Children’s Research Institute, Seattle, WA 98101; and Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195

The splenic B cell compartment is comprised of two major, functionally distinct, mature B cell subsets, i.e., follicular mature (FM) and marginal zone (MZ) B cells. Whereas MZ B cells exhibit a robust proliferative response following stimulation with the TLR4 ligand LPS, FM B cells display markedly delayed and reduced levels of proliferation to the identical stimulus. The current study was designed to identify a potential mechanism(s) accounting for this differential responsiveness. In contrast to the delay in cell cycle entry, FM and MZ B cells exhibited nearly identical LPS-driven alterations in the expression level of cell surface activation markers. Furthermore, both the NF-B and mTOR signaling cascades were similarly activated by LPS stimulation in FM vs MZ B cells, while inducible activation of ERK and AKT were nearly absent in both subsets. MZ B cells, however, exhibited higher basal levels of phospho-AKT and pS6, consistent with a preactivated status. Importantly, both basal and LPS activation-induced c-myc expression was markedly reduced in FM vs MZ B cells and enforced c-myc expression fully restored the defective proliferative response in FM B cells. These data support a model wherein TLR responses in FM B cells are tightly regulated by limiting c-myc levels, thereby providing an important checkpoint to control nonspecific FM B cell activation in the absence of cognate Ag.

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 Support for this work has included the Elizabeth Campbell Endowment (to A.M.B.), National Cancer Institute Immunology Training Grant (to A.D.B.), Cancer Research Institute Immunology Training Grant (to S.F.A.), and National Institutes of Health Grants HD37091, CA81140, and HL075453 (to D.J.R.).

² Current address: Department of Pediatric Pneumology and Neonatology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, Germany.

³ Address correspondence and reprint requests to Dr. David J. Rawlings, Center for Immunology and Immunotherapies, Seattle Children’s Research Institute, 1900 Ninth Avenue, Seattle, WA 98101. E-mail address: drawling{at}u.washington.edu

⁴ Abbreviations used in this paper: FM, follicular mature; MZ, marginal zone; tg, transgenic; TNP, trinitrophenyl; DAPI, 4',6-diamidino-2-phenylindole; MZp, precursor MZ; β₂m, β₂-microglobulin; MHC II, MHC class II; wt, wild type; Q-PCR, quantitative PCR; mTOR, mammalian target of rapamycin.