Neutrophils use opsonizing antibodies to enhance the clearance of intruding microbes. Recent studies indicate that splenic neutrophils also induce antibody production by providing helper signals to B ...cells lodged in the MZ of the spleen. Here, we discuss the B cell helper function of neutrophils in the context of growing evidence indicating that neutrophils function as sophisticated regulators of innate and adaptive immune responses.
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.
Exosomes, nano-sized membrane vesicles, are released by various cells and are found in many human body fluids. They are active players in intercellular communication and have immune-suppressive, ...immune-regulatory, and immune-stimulatory functions. EBV is a ubiquitous human herpesvirus that is associated with various lymphoid and epithelial malignancies. EBV infection of B cells in vitro induces the release of exosomes that harbor the viral latent membrane protein 1 (LMP1). LMP1 per se mimics CD40 signaling and induces proliferation of B lymphocytes and T cell-independent class-switch recombination. Constitutive LMP1 signaling within B cells is blunted through the shedding of LMP1 via exosomes. In this study, we investigated the functional effect of exosomes derived from the DG75 Burkitt's lymphoma cell line and its sublines (LMP1 transfected and EBV infected), with the hypothesis that they might mimic exosomes released during EBV-associated diseases. We show that exosomes released during primary EBV infection of B cells harbored LMP1, and similar levels were detected in exosomes from LMP1-transfected DG75 cells. DG75 exosomes efficiently bound to human B cells within PBMCs and were internalized by isolated B cells. In turn, this led to proliferation, induction of activation-induced cytidine deaminase, and the production of circle and germline transcripts for IgG1 in B cells. Finally, exosomes harboring LMP1 enhanced proliferation and drove B cell differentiation toward a plasmablast-like phenotype. In conclusion, our results suggest that exosomes released from EBV-infected B cells have a stimulatory capacity and interfere with the fate of human B cells.
New helping friends for B cells Cerutti, Andrea; Puga, Irene; Cols, Montserrat
European Journal of Immunology,
August 2012, 2012-Aug, 2012-08-00, 20120801, Letnik:
42, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Over the past decade, a growing recognition of the importance of neutralizing antibodies in host defense combined with the success of B‐cell depletion therapies in treating auto‐immune disorders has ...led to an increased focus on better understanding the pathways underpinning B‐cell antibody production. In general, B cells require cognate interaction with T helper cells in the germinal center of lymphoid follicles to generate protective antibodies. However, recent evidence shows that B cells receive additional help from invariant natural killer T cells, dendritic cells, and various granulocytes, including neutrophils, eosinophils, and basophils. These innate immune cells enhance T‐cell‐dependent antibody responses by delivering B‐cell helper signals both in the germinal center and at postgerminal center lymphoid sites such as the bone marrow. In addition to enhancing and complementing the B‐cell helper activity of canonical T cells, invariant natural killer T cells, dendritic cells, and granulocytes can deliver T cell‐independent B‐cell helper signals at the mucosal interface and in the marginal zone of the spleen to initiate rapid innate‐like antibody responses. Here, we discuss recent advances in the role of adaptive and innate B‐cell helper signals in antibody diversification and production.
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-kappaB 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-kappaB 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.
Protective responses to microorganisms involve the nonspecific but rapid defence mechanisms of the innate immune system, followed by the specific but slow defence mechanisms of the adaptive immune ...system. Located as sentinels at the interface between the circulation and lymphoid tissue, splenic marginal zone B cells rapidly respond to blood-borne antigens by adopting 'crossover' defensive strategies that blur the conventional boundaries of innate and adaptive immunity. This Review discusses how marginal zone B cells function as innate-like lymphocytes that mount rapid antibody responses to both T cell-dependent and T cell-independent antigens. These responses require the integration of activation signals from germline-encoded and somatically recombined receptors for microorganisms with helper signals from effector cells of the innate and adaptive immune systems.
The past 20 years have seen a growing interest over the control of adaptive immune responses by the innate immune system. In particular, considerable attention has been paid to the mechanisms by ...which antigen-primed dendritic cells orchestrate the differentiation of T cells. Additional studies have elucidated the pathways followed by T cells to initiate immunoglobulin responses in B cells. In this review, we discuss recent advances on the mechanisms by which intestinal bacteria, epithelial cells, dendritic cells, and macrophages cross talk with intestinal T cells and B cells to induce frontline immunoglobulin A class switching and production.
Adaptive co‐evolution of mammals and bacteria has led to the establishment of complex commensal communities on mucosal surfaces. In spite of having available a wealth of immune‐sensing and effector ...mechanisms capable of triggering inflammation in response to microbial intrusion, mucosal immune cells establish an intimate dialogue with microbes to generate a state of hyporesponsiveness against commensals and active readiness against pathogens. A key component of this homeostatic balance is IgA, a noninflammatory antibody isotype produced by mucosal B cells through class switching. This process involves activation of B cells by IgA‐inducing signals originating from mucosal T cells, dendritic cells, and epithelial cells. Here, we review the mechanisms by which mucosal B cells undergo IgA diversification and production and discuss how the study of primary immunodeficiencies facilitates better understanding of mucosal IgA responses in humans.
The intestinal mucosa contains large communities of commensal bacteria that process otherwise indigestible food components, synthesize essential vitamins, stimulate the maturation of the immune ...system, and form an ecologic niche that prevents the growth of pathogenic species. Conversely, the intestine provides the commensals with a stable habitat rich in energy derived from the ingested food. A delicate homeostatic balance maintains this mutualistic relationship without triggering a destructive inflammatory response. Commensals orchestrate intestinal homeostasis by entertaining an intimate dialogue with epithelial cells and immune cells lodged in the mucosa. Such a dialogue generates finely tuned signaling programs that ensure a state of hyporesponsiveness against noninvasive commensals and a state of active readiness against invasive pathogens. In this dialogue epithelial cells function as “interpreters” that continuously translate microbial messages to “instruct” immune cells as to the antigenic composition of the intestinal lumen. This education process initiates sophisticated defensive strategies that comprise massive production of IgA, a noninflammatory mucosal antibody class that generates immunity while preserving homeostasis.
Mature B cells generate protective immunity by undergoing immunoglobulin (Ig) class switching and somatic hypermutation, two Ig gene-diversifying processes that usually require cognate interactions ...with T cells that express CD40 ligand. This T-cell-dependent pathway provides immunological memory but is relatively slow to occur. Thus, it must be integrated with a faster, T-cell-independent pathway for B-cell activation through CD40 ligand-like molecules that are released by innate immune cells in response to microbial products. Here, we discuss recent advances in our understanding of the interplay between the innate immune system and B cells, particularly “frontline” B cells located in the marginal zone of the spleen and in the intestine.
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