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.

Innate lymphoid cells (ILCs) regulate stromal, epithelial and immune cells, but their impact on B cells remains unclear. We identified RORγt+ ILCs nearby the marginal zone (MZ), a splenic compartment containing innate-like B cells that respond to circulating T cell-independent (TI) antigens. Spenic ILCs established a bidirectional crosstalk with MAdCAM-1+ marginal reticular cells by providing tumor necrosis factor (TNF) and lymphotoxin, and activated MZ B cells via BAFF, CD40 ligand and the Notch ligand, Delta-like 1. Splenic ILCs further helped MZ B cells and their plasma cell progeny by co-opting neutrophils through the release of GM-CSF. Consequently, ILC depletion 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 and circulatory systems.

Summary Complex and diverse communities of bacteria establish mutualistic and symbiotic relationships with the gut after birth. The intestinal immune system responds to bacterial colonization by acquiring a state of hypo-responsiveness against commensals and active readiness against pathogens. The resulting homeostatic balance involves a continuous dialog between the microbiota and lymphocytes with the intermediation of epithelial and dendritic cells. This dialog causes massive production of immunoglobulin A (IgA), a non-inflammatory antibody specialized in mucosal protection. Here, we discuss recent advances on the regulation of intestinal IgA responses and their role in host-microbe interaction.

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SummarySecretory 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.

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IntroductionHuman cytomegalovirus (HCMV) infection is highly prevalent in healthy persons and the virus remains in a lifelong latent state, undergoing occasional reactivation and causing an important morbidity in immunocompromised patients. 1 An effective defense against CMV infection requires the participation of both T and NK cells. 2 To escape T cell-mediated recognition, CMV interferes with the expression of major histocompatibility complex molecules and antigen presentation. 3 The loss of human leukocyte antigen (HLA) class I molecules in infected cells impairs the engagement of inhibitory receptors, thus promoting the activation of NK-cell effector functions. Reciprocally, the virus has developed different strategies to escape NK-cell surveillance, preventing the expression of ligands for some activating receptors (ie, NKG2D, DNAM-1) 4-9 or selectively maintaining inhibitory receptors for HLA class I molecules engaged. The UL18 glycoprotein binds with high affinity to the LILRB1 inhibitory receptor expressed in different leukocytes 10 ; yet, formal experimental evidence for its function in immune evasion remains elusive. 11 In the same line, a leader signal peptide of the UL40 HCMV protein was shown to stabilize the surface expression of HLA-E, thus repressing NK-cell activation by engagement of the inhibitory CD94/NKG2A receptor. 12,13 On the other hand, the NK-cell subset bearing the CD94/NKG2C triggering molecule tends to expand in peripheral blood from HCMV ϩ persons 14 and on in vitro coculture of peripheral blood mononuclear cells (PBMCs) with HCMV-infected fibroblasts. 15 A CD94/NKG2C ϩ NK lymphocytosis was detected in a patient with a selective T-cell deficiency, coinciding with an acute HCMV infection and associated with a reduction of viremia. 16 Altogether, these results suggest that the CD94/NKG2C ϩ NK-cell subset may play an active role in the response to HCMV.Information on the nature of NK-cell receptor (NKR)-ligand interactions involved in the response against HCMV-infected cells is scarce, and most studies have been performed in infected fibroblasts, not fully representative of the different cell types susceptible to in vivo infection. Cells of the myeloid lineage are considered reservoirs for HCMV latency, and differentiation of myeloid progenitors to dendritic cells (DCs) may reactivate the virus. 17 Furthermore, monocyte-derived DCs (moDCs) appear susceptible to in vitro HCMV infection by endothelial cell (EC)-adapted viral strains. 18 Infection of moDCs has been reported to impair their maturation, inhibiting surface expression of major histocompatibility complex class I and II, costimulatory molecules, and chemokine receptors (ie, CCR1 and CCR5), thus interfering with the development of virus-specific T-cell responses. [19][20][21] Beyond their key role in antigen presentation, DCs may establish a cross-talk with NK cells that reciprocally regulates their Submitted August 9, 2010; accepted October 13, 2010. Prepublished online as Blood First Edition paper, October 28, 2010; DOI 10.118...

Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G), a human cytidine deaminase, is a potent inhibitor of HIV replication. To explore a possible role of this protein in modulating in vivo susceptibility to HIV infection, we analyzed APOBEC3G expression in HIV-exposed seronegative individuals, HIV-seropositive patients, and healthy control subjects. The results showed that the expression of APOBEC3G is significantly increased in peripheral blood mononuclear cells (PBMCs)--mainly CD14(+) cells--and in cervical tissues of HIV-exposed seronegative individuals. Higher APOBEC3G expression correlated with a reduced susceptibility of PBMCs to in vitro infection with the HIV-1(Ba-L) R5 strain. APOBEC3G could be important in modulating in vivo susceptibility to sexually transmitted HIV infection.