Meimei Shan

B cell–helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen

Neutrophils utilize immunoglobulins (Igs) to clear antigen, but their role in Ig production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T-independent Ig responses to circulating antigen. Neutrophils colonized peri-MZ areas after post-natal mucosal colonization by microbes and enhanced their B-helper function upon receiving reprogramming signals from splenic sinusoidal endothelial cells, including interleukin 10 (IL-10). Splenic neutrophils induced Ig class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism involving the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and less preimmune Igs to T-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial Ig defense by interacting with MZ B cells.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.

Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals

Guardian of the Gut The intestine is able to tolerate continual exposure to large amounts of commensal bacteria and foreign food antigens without triggering an inappropriate inflammatory immune response. In the large intestine, this immunological tolerance is thought to occur via a physical separation between environment and host imposed by a continuous mucous layer built up from the secreted mucin protein, MUC2. However, in the small intestine, this mucous layer is porous, necessitating an additional layer of immune control. Shan et al. (p. 447, published online 26 September; see the Perspective by Belkaid and Grainger) now report that in the small intestine, MUC2 plays an active role in immunological tolerance by activating a transcription factor in resident dendritic cells, thereby selectively blocking their ability to launch an inflammatory response. This work identifies MUC2 as a central mediator of immune tolerance to maintain homeostasis in the gut and possibly at other mucosal surfaces in the body. Mucus not only forms a physical barrier in the intestine but also promotes immunological tolerance of bacteria and foods. [Also see Perspective by Belkaid and Grainger] A dense mucus layer in the large intestine prevents inflammation by shielding the underlying epithelium from luminal bacteria and food antigens. This mucus barrier is organized around the hyperglycosylated mucin MUC2. Here we show that the small intestine has a porous mucus layer, which permitted the uptake of MUC2 by antigen-sampling dendritic cells (DCs). Glycans associated with MUC2 imprinted DCs with anti-inflammatory properties by assembling a galectin-3–Dectin-1–FcγRIIB receptor complex that activated β-catenin. This transcription factor interfered with DC expression of inflammatory but not tolerogenic cytokines by inhibiting gene transcription through nuclear factor κB. MUC2 induced additional conditioning signals in intestinal epithelial cells. Thus, mucus does not merely form a nonspecific physical barrier, but also constrains the immunogenicity of gut antigens by delivering tolerogenic signals.

The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88

BAFF and APRIL are innate immune mediators that trigger immunoglobulin (Ig) G and IgA class switch recombination (CSR) in B cells by engaging the receptor TACI. The mechanism underlying CSR signaling by TACI remains unknown. Here, we found that the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor protein that activates NF-κB signaling pathways via a Toll-interleukin-1 receptor (TIR) domain. TACI lacks a TIR domain, yet triggered CSR via the DNA-editing enzyme AID by activating NF-κB through a TLR-like MyD88–IRAK-1-IRAK-4–TRAF6–TAK1 pathway. TACI-induced CSR was impaired in mice and humans lacking MyD88 or IRAK-4, indicating that MyD88 controls a B cell-intrinsic, TIR-independent, TACI-dependent pathway for Ig diversification.BAFF and APRIL are innate immune mediators that trigger immunoglobulin G (IgG) and IgA class-switch recombination (CSR) in B cells by engaging the receptor TACI. The mechanism that underlies CSR signaling by TACI remains unknown. Here we found that the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor that activates transcription factor NF-κB signaling pathways via a Toll–interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggered CSR via the DNA-editing enzyme AID by activating NF-κB through a Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway. TACI-induced CSR was impaired in mice and humans lacking MyD88 or the kinase IRAK4, which indicates that MyD88 controls a B cell–intrinsic, TIR-independent, TACI-dependent pathway for immunoglobulin diversification.

Microbiota regulate the ability of lung dendritic cells to induce IgA class-switch recombination and generate protective gastrointestinal immune responses.

Ruane et al. demonstrate a role for the microbiota in modulating protective immunity to intranasal vaccination via the ability of lung dendritic cells to induce B cell IgA class switching.

The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

Cerutti and collaborators show that the humoral arms of the innate and adaptive immune systems are functionally interconnected by pentraxin 3, a soluble pattern recognition receptor that couples innate immune recognition with antibody-inducing function.

Erratum: B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen (Nature Immunology (2012) 13 (170-180))

Irene Puga, Montserrat Cols, Carolina M Barra, Bing He, Linda Cassis, Maurizio Gentile, Laura Comerma, Alejo Chorny, Meimei Shan, Weifeng Xu, Giuliana Magri, Daniel M Knowles, Wayne Tam, April Chiu, James B Bussel, Sergi Serrano, José Antonio Lorente, Beatriz Bellosillo, Josep Lloreta, Nuria Juanpere, Francesc Alameda, Teresa Baró, Cristina Díaz de Heredia, Núria Torán, Albert Català, Montserrat Torrebadell, Claudia Fortuny, Victoria Cusí, Carmen Carreras, George A Diaz, J Magarian Blander, Claire-Michèle Farber, Guido Silvestri, Charlotte Cunningham-Rundles, Michaela Calvillo, Carlo Dufour, Lucia Dora Notarangelo, Vassilios Lougaris, Alessandro Plebani, Jean-Laurent Casanova, Stephanie C Ganal, Andreas Diefenbach, Juan Ignacio Aróstegui, Manel Juan, Jordi Yagüe, Nizar Mahlaoui, Jean Donadieu, Kang Chen & Andrea Cerutti Nat. Immunol. 13, 170–180 (2012); published online 25 December 2011; corrected after print 12 July 2013