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Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
Both constitutive Ig secretion by long-lived plasma cells (PC) and the recurrent differentiation of memory (mem) B cells into PC contribute to the maintenance of serologic mem. However, the relative contribution of each is unknown. In this study, we describe a novel population of human postswitched mem B cells that rapidly differentiate into PC and thus contribute to serologic mem. These IgG+ B cells reside in the region of human spleen analogous to the murine marginal zone and have not previously been examined. These cells are highly responsive to IL-21 in the context of CD40 stimulation. Uniquely, IgG+ marginal zone analog B cells are exquisitely sensitive to the combination of IL-21 and B cell-activating factor belonging to the TNF family (BAFF/BLyS) that synergize in the absence of further costimulation to induce up-regulation of B lymphocyte-induced maturation protein-1 and drive PC differentiation. Other cytokine combinations are not active in this regard. This is the first demonstration that this unique population of mem B cells can respond specifically and exclusively to IL-21 and BAFF/BLyS by differentiating into IgG-secreting PC, and thus contributing to serologic mem in an Ag-independent manner.
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 the intramural program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Rachel Ettinger, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Room 6D-47B, Bethesda, MD 20892. E-mail address: ettingerr{at}mail nih.gov
3 Abbreviations used in this paper: mem, memory; PC, plasma cell; MZ, marginal zone; TI-2, T-independent type 2 Ag; MZA, MZ analog; CSR, class switch recombination; AID, activation induced cytidine deaminase; BLIMP-1, B lymphocyte-induced maturation protein-1; DC, dendritic cell; BAFFR, BAFF/BLyS receptor; TACI, transmembrane activator and calcium modulator cyclophilin ligand interactor; BCMA, B cell maturation Ag; APRIL, a proliferation-inducing ligand; FO, follicular; 
-2M, -2 microglobulin; AP, alkaline phosphatase; IHC, immunohistochemistry; AF, Alexa Fluor; LYVE, lymphatic endothelial hyaluronan receptor; FDC, follicular DC.
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