Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell–independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell–helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell–independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.
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We thank J. Farrés, J. Yélamos, A. Muntasell and M. López-Botet (Institut Municipal d'Investigació Mèdica-Hospital del Mar) for reagents, samples and discussions; N. Romo, S. Bascones, E. Ramirez and O. Fornas for help with cell sorting; and S. Mojal for help with the statistical analysis. Supported by Ministerio de Ciencia e Innovación (SAF 2008-02725 to A.Ce.), the US National Institutes of Health (R01 AI074378, P01 AI61093, U01 AI95613 and P01 096187 to A.Ce.), the European Commission (EUROPADnet HEALTH-F2-2008-201549 to A.Ce.), the Juan de la Cierva Program (I.P. and G.M.), the Instituto de Salud Carlos III (C.M.B. and M.G. and A.Ch.), the Ministerio de Ciencia e Innovación (C.M.B. and M.G.), Yerkes National Primate Research Center (P51 RR00165 to G.S.) and Fondazione C. Golgi di Brescia, Associazione Immunodeficienze Primitive (A.P.).
The authors declare no competing financial interests.
Supplementary Figures 1–22 and Tables 1–6 (PDF 2223 kb)
NBH cells form NET-like structures to interact with splenic MZ B cells. Confocal microscopy and three-dimensional animation of a spleen section stained for elastase (green), IgD (red) and DNA (blue). The movie was generated by acquiring up to 14 x,y planes with 0.3 μm z spacing. Original magnification, x40. One of three experiments yielding similar results. (AVI 17483 kb)
NBH cells spontaneously form DNA-containing NET-like projections. Confocal microscopy and three-dimensional animation of NBH cells stained for elastase (green) and DNA (blue). The movie was generated by acquiring up to 25 x,y planes with 0.3 μm z spacing. Original magnification, x63; digital magnification, x2. One of three experiments yielding similar results. (AVI 9943 kb)
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