Laura Comerma

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.

Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells

Innate lymphoid cells (ILCs) regulate stromal cells, epithelial cells and cells of the immune system, but their effect on B cells remains unclear. Here we identified RORγt+ ILCs near the marginal zone (MZ), a splenic compartment that contains innate-like B cells highly responsive to circulating T cell–independent (TI) antigens. Splenic ILCs established bidirectional crosstalk with MAdCAM-1+ marginal reticular cells by providing tumor-necrosis factor (TNF) and lymphotoxin, and they stimulated MZ B cells via B cell–activation factor (BAFF), the ligand of the costimulatory receptor CD40 (CD40L) and the Notch ligand Delta-like 1 (DLL1). Splenic ILCs further helped MZ B cells and their plasma-cell progeny by coopting neutrophils through release of the cytokine GM-CSF. Consequently, depletion of ILCs impaired both pre- and post-immune TI antibody responses. Thus, ILCs integrate stromal and myeloid signals to orchestrate innate-like antibody production at the interface between the immune system and circulatory system.

Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals

Summary Secretory immunoglobulin A (SIgA) enhances host‐microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut‐specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell‐independent or T cell‐dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus‐embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA‐only‐coated or uncoated bacteria. Thus, SIgM may emerge from pre‐existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus. Graphical Abstract Figure. No Caption available. HighlightsIgM+ PCs generating SIgM are relatively abundant in human but not mouse gutIgM+ PCs clonally relate to a large gut repertoire of memory IgM+ B cellsGut memory IgM+ B cells express a tissue‐specific signature and can switch to IgAHuman but not mouse SIgM binds a highly diverse microbiota dually coated by SIgA &NA; Magri et al. found that the human gut includes a large memory IgM+ B cell repertoire clonally related to plasma cells mounting SIgM responses against mucus‐embedded commensals co‐targeted by SIgA. Dually coated bacteria are detected in humans but not mice and show increased diversity and richness compared to SIgA‐only‐coated or uncoated bacteria.

mTOR intersects antibody-inducing signals from TACI in marginal zone B cells

Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin G (IgG) class switching, and plasmablast differentiation through a rapamycin-sensitive pathway that integrates metabolic and antibody-inducing transcription programs, including NF-κB. Disruption of TACI–mTOR interaction by rapamycin, truncation of the MyD88-binding domain of TACI, or B-cell-conditional mTOR deficiency interrupts TACI signaling via NF-κB and cooperation with TLRs, thereby hampering IgG production to T-cell-independent antigens but not B-cell survival. Thus, mTOR drives innate-like antibody responses by linking proximal TACI signaling events with distal immunometabolic transcription programs.Marginal zone B cells differentiate into plasma cells rapidly in response to T-cell-independent antigens, but how they do so is not clear. Here the authors show TACI cooperates with TLR signalling to drive mTOR activity and subsequent class switching and plasmablast differentiation.

LMO2-negative Expression Predicts the Presence of MYC Translocations in Aggressive B-Cell Lymphomas.

MYC translocation is a defining feature of Burkitt lymphoma (BL), and the new category of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 translocations, and occurs in 6% to 15% of diffuse large B-cell lymphomas (DLBCLs). The low incidence of MYC translocations in DLBCL makes the genetic study of all these lymphomas cumbersome. Strategies based on an initial immunophenotypic screening to select cases with a high probability of carrying the translocation may be useful. LMO2 is a germinal center marker expressed in most lymphomas originated in these cells. Mining gene expression profiling studies, we observed LMO2 downregulation in BL and large B-cell lymphoma (LBCL) with MYC translocations, and postulated that LMO2 protein expression could assist to identify such cases. We analyzed LMO2 protein expression in 46 BLs and 284 LBCL. LMO2 was expressed in 1/46 (2%) BL cases, 146/268 (54.5%) DLBCL cases, and 2/16 (12.5%) high-grade B-cell lymphoma cases with MYC and BCL2 and/or BCL6 translocations. All BLs carried MYC translocation (P<0.001), whereas LMO2 was only positive in 6/42 (14%) LBCL with MYC translocation (P<0.001). The relationship between LMO2 negativity and MYC translocation was further analyzed in different subsets of tumors according to CD10 expression and cell of origin. Lack of LMO2 expression was associated with the detection of MYC translocations with high sensitivity (87%), specificity (87%), positive predictive value and negative predictive value (74% and 94%, respectively), and accuracy (87%) in CD10+ LBCL. Comparing LMO2 and MYC protein expression, all statistic measures of performance of LMO2 surpassed MYC in CD10+ LBCL. These findings suggest that LMO2 loss may be a good predictor for the presence of MYC translocation in CD10+ LBCL.

Secreted IgD Amplifies Humoral T Helper 2 Cell Responses by Binding Basophils via Galectin-9 and CD44

Graphical Abstract Figure. No caption available. SUMMARY B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well‐understood effector functions. In contrast, the role of secreted IgD remains mysterious. We found that some B cells generated IgD‐secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44‐binding protein galectin‐9. When engaged by antigen, basophil‐bound IgD increased basophil secretion of interleukin‐4 (IL‐4), IL‐5, and IL‐13, which facilitated the generation of T follicular helper type 2 cells expressing IL‐4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil‐bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co‐ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2‐mediated immunity against common environmental soluble antigens. HIGHLIGHTSIgD interacts with basophils through the CD44‐binding protein galectin‐9IgD ligation by antigen elicits basophil release of Th2 cell‐associated cytokinesIgD‐activated basophils enhance B cell production of IgG1 and IgEIgD interferes with IgE‐mediated basophil degranulation &NA; The function of IgD has been mysterious. Shan et al. find that IgD recognized food antigens and targeted basophils through galectin‐9. IgD ligation by antigen induced basophil secretion of IL‐4, IL‐5, and IL‐13, which amplified Th2 cell‐mediated IgG1 and IgE production by B cells. IgD also constrained IgE‐mediated basophil degranulation.

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