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Divergent Effects of BAFF on Human Memory B Cell Differentiation into Ig-Secreting Cells¹

Department of Immunology, Mayo Clinic College of Medicine, Mayo Graduate School, Rochester, MN 55905

B cell-activating factor belonging to the TNF family (BAFF) plays a critical role in B cell maturation, yet its precise role in B cell differentiation into Ig-secreting cells (ISCs) remains unclear. In this study, we find that upon isolation human naive and memory B (MB) cells have prebound BAFF on their surface, whereas germinal center (GC) B cells lack detectable levels of prebound BAFF. We attribute their lack of prebound BAFF to cell activation, because we demonstrate that stimulation of naive and MB cells results in the loss of prebound BAFF. Furthermore, the absence of prebound BAFF on GC B cells is not related to a lack of BAFF-binding receptors or an inability to bind exogenous BAFF. Instead, our data suggest that accessibility to soluble BAFF is limited within GCs, perhaps to prevent skewing of the conventional B cell differentiation program. In support of this concept, whereas BAFF significantly enhances ISC differentiation in response to T cell-dependent activation, we report for the first time the ability of BAFF to considerably attenuate ISC differentiation of MB cells in response to CpG stimulation, a form of T cell-independent activation. Our data suggest that BAFF may be providing regulatory signals during specific T cell-independent events, which protect the balance between MB cells and ISCs outside GCs. Taken together, these data define a complex role for BAFF in humoral immune responses and show for the first time that BAFF can also play an inhibitory role in B cell differentiation.

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 RO1 CA 105258 (awarded to D.F.J.) and Predoctoral Fellowship F31 AI 61838 (awarded to J.R.D.).

² Address correspondence and reprint requests to Dr. Diane F. Jelinek, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. E-mail address: jelinek.diane{at}mayo.edu

³ Abbreviations used in this paper: MB, memory B; 40L/c, CD40L/cytokine; anti-Ig/40L/c, anti-Ig/CD40L/cytokine; BAFF, B cell-activating factor belonging to the TNF family; BBR, BAFF-binding receptor; BCMA, B cell maturation Ag; cIg, cytoplasmic Ig; CpG/c, CpG/cytokine; DPBS, Dulbecco’s PBS; FDC, follicular dendritic cell; GC, germinal center; ISC, Ig-secreting cell; MFI, median fluorescence intensity; PB, peripheral blood; PI, propidium iodide; rhBAFF, human rBAFF; rhBCMA, human rBCMA; rhBR3, human BLyS receptor 3; SA/c, Staphylococcus aureus Cowan A plus IL-2; TACI, transmembrane activator and calcium-modulating cyclophilin ligand interactor; TD, T cell dependent; TI, T cell independent.

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