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Imprinting the Fate of Antigen-Reactive B Cells through the Affinity of the B Cell Receptor¹

Brian P. O’Connor^2,*, Laura A. Vogel^2,, Weijun Zhang^*, William Loo, Danielle Shnider, Evan F. Lind^*, Michelle Ratliff, Randolph J. Noelle^* and Loren D. Erickson^3,

^* Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756; Department of Biological Sciences, Illinois State University, Normal, IL 61790; and Department of Microbiology, University of Virginia, Charlottesville, VA 22908

Long-lived plasma cells (PCs) and memory B cells (B_mem) constitute the cellular components of enduring humoral immunity, whereas short-lived PCs that rapidly produce Ig correspond to the host’s need for immediate protection against pathogens. In this study we show that the innate affinity of the BCR for Ag imprints upon naive B cells their differentiation fate to become short- or long-lived PCs and B_mem. Using BCR transgenic mice with varying affinities for Ag, naive B cells with high affinity lose their capacity to form germinal centers (GCs), develop neither B_mem nor long-lived PCs, and are destined to a short-lived PC fate. Moderate affinity interactions result in hastened GC responses, and differentiation to long-lived PCs, but B_mem remain extinct. In contrast, lower affinity interactions show tempered GCs, producing B_mem and affinity-matured, long-lived PCs. Thus, a continuum of elementary to comprehensive humoral immune responses exists that is controlled by inherent BCR affinity.

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 Grants AI-26296 and AI-42234 (to R.J.N.), National Center for Research Resources, Centers of Biomedical Research Excellence Grants AR-052902 and P20RR16437 (to L.D.E.), and grants from the Arthritis Foundation (to L.D.E.) and the American Federation of Aging Research and Pfizer (to L.A.V.).

² B.P.O. and L.A.V. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Loren D. Erickson, Department of Microbiology, University of Virginia, Jordan Hall, Room 7034, 1300 Jefferson Park Avenue, Charlottesville, VA 22908. E-mail address: lde9w{at}virginia.edu

⁴ Abbreviations used in this paper: GC, germinal center; AID, activation-induced cytidine deaminase; BM, bone marrow; B_mem, memory B cell; CT, cycle threshold; HEL, hen egg lysozyme; int, intermediate; KLH, keyhole limpet hemocyanin; NIP, (4-hydroxy-5-iodo-3-nitrophenyl)acetyl; NP, (4-hydroxy-3-nitrophenyl)acetyl; PC, plasma cell; PC_pre, PC precursor; PNA, peanut agglutinin; QM, quasi-monoclonal; SHM, somatic hypermutation; TD, T cell dependent; Tg, transgenic; 1°, primary; 2°, secondary.

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