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Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα₃) produced by RORγt⁺ innate lymphoid cells (ILCs) controls T cell-dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin β (LTα₁β₂) produced by RORγt⁺ ILCs is critical for T cell-independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTα in RORγt⁺ cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxin s produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition.

Dendritic cells in immune surveillance Christine Moussion and Jean-Philippe Girard report that dendritic cells in the immune system have an unexpected immune surveillance role in lymphocyte recirculation during homeostasis. Lymphotoxin ligands derived from dendritic cells promote the growth of high endothelial venules — blood vessels specialized in lymphocyte recruitment — which control the entry of naive lymphocytes from the blood into lymph nodes. While patrolling the body in search of foreign antigens, naive lymphocytes continuously circulate from the blood, through the lymph nodes, into the lymphatic vessels and back to the blood 1 , 2 . This process, called lymphocyte recirculation, provides the body with effective immune surveillance for foreign invaders and for alterations to the body’s own cells. However, the mechanisms that regulate lymphocyte recirculation during homeostasis remain incompletely characterized. Here we show that dendritic cells (DCs), which are well known for their role in antigen presentation to T lymphocytes 3 , control the entry of naive lymphocytes to lymph nodes by modulating the phenotype of high endothelial venules (HEVs), which are blood vessels specialized in lymphocyte recruitment 2 , 4 , 5 . We found that in vivo depletion of CD11c + DCs in adult mice over a 1-week period induces a reduction in the size and cellularity of the peripheral and mucosal lymph nodes. In the absence of DCs, the mature adult HEV phenotype reverts to an immature neonatal phenotype, and HEV-mediated lymphocyte recruitment to lymph nodes is inhibited. Co-culture experiments showed that the effect of DCs on HEV endothelial cells is direct and requires lymphotoxin-β-receptor-dependent signalling. DCs express lymphotoxin, and DC-derived lymphotoxin is important for lymphocyte homing to lymph nodes in vivo . Together, our results reveal a previously unsuspected role for DCs in the regulation of lymphocyte recirculation during immune surveillance.

Ectopic bronchus-associated lymphoid tissue can form in lungs after pulmonary infection. Randall and colleagues show that aerosolized lipopolysaccharide induces the formation of this tissue in neonatal mice by a process dependent on interleukin 17. Ectopic or tertiary lymphoid tissues, such as inducible bronchus-associated lymphoid tissue (iBALT), form in nonlymphoid organs after local infection or inflammation. However, the initial events that promote this process remain unknown. Here we show that iBALT formed in mouse lungs as a consequence of pulmonary inflammation during the neonatal period. Although we found CD4 + CD3 − lymphoid tissue–inducer cells (LTi cells) in neonatal lungs, particularly after inflammation, iBALT was formed in mice that lacked LTi cells. Instead, we found that interleukin 17 (IL-17) produced by CD4 + T cells was essential for the formation of iBALT. IL-17 acted by promoting lymphotoxin-α-independent expression of the chemokine CXCL13, which was important for follicle formation. Our results suggest that IL-17-producing T cells are critical for the development of ectopic lymphoid tissues.

Lymphotoxin-alpha (LTα3) is a soluble cytokine of the TNF superfamily. Its role in inflammation and arthritis is not well known. Macrophages are important in K/BxN Serum-Transfer Arthritis (STA) and rheumatoid arthritis (RA). Anti-TNF monoclonal antibodies as well as etanercept (ETA), a soluble TNF receptor II that also neutralizes LTα3, are efficient in the treatment of RA. Objectives: To evaluate the role of LTα3 in macrophage phenotypes and in arthritis. Methods: Macrophages were cultured in the presence of recombinant LTα3, and their phenotypes were studied. The clinical effect of blocking LTα3 in STA was evaluated, as well as the effect of switching from anti-TNF monoclonal antibodies to etanercept in the “ROC” register of RA patients. Results: We showed that recombinant LTα3 was capable of directing mouse and human macrophages towards a pro-inflammatory “M1” phenotype. In K/BxN STA, ETA decreased clinical score and joint swelling. Anti-LTα3 reduced arthritis only in TNF-KO mice, indicating that the effect of LTα3 was visible in the absence of TNF. The “ROC” register indicated that switching anti-TNF mAb to ETA did not induce clinical and biological improvement in RA. Conclusion: We show a pro-inflammatory role for LTα3 in murine and human macrophages. The neutralization of both TNF and LTα3 is not beneficial in the treatment of RA.

Key Points 19 ligands and 29 receptors that belong to the tumour-necrosis factor (TNF) superfamily have been identified. At the cellular level TNF-superfamily members promote either apoptosis, proliferation, survival or differentiation. The main signals transduced by the TNF-superfamily members include activation of nuclear factor-κB (NF-κB), JUN N-terminal kinase, p38 mitogen activated protein kinase and ERK1/ERK2. Members of the TNF superfamily mediate haematopoiesis, immune surveillance, tumour regression and protection from infection. Members of the TNF superfamily mediate inflammation, autoimmune diseases, rheumatoid arthritis, tumour metastasis, septic shock and osteoporosis. TNF and its inhibitors have been approved as therapeutics. Two different tumour-necrosis factors (TNFs), first isolated in 1984, were found to be cytotoxic to tumour cells and to induce tumour regression in mice. Research during the past two decades has shown the existence of a superfamily of TNF proteins consisting of 19 members that signal through 29 receptors. These ligands, while regulating normal functions such as immune responses, haematopoiesis and morphogenesis, have also been implicated in tumorigenesis, transplant rejection, septic shock, viral replication, bone resorption, rheumatoid arthritis and diabetes; so indicating their role as 'double-edged swords'. These cytokines either induce cellular proliferation, survival, differentiation or apoptosis. Blockers of TNF have been approved for human use in treating TNF-linked autoimmune diseases in the United States and other countries.

Mouse lymphoid tissue–inducer (LTi) cells require the transcription factor RORγt. Cupedo's group identifies RORγt + human LTi cell equivalents as committed natural killer cell precursors, and teams led by Vivier and Diefenbach describe RORγt-expressing interleukin 22–producing natural killer cells in mouse gut. The human body contains over 500 individual lymph nodes, yet the biology of their formation is poorly understood. Here we identify human lymphoid tissue–inducer cells (LTi cells) as lineage-negative RORC + CD127 + cells with the functional ability to interact with mesenchymal cells through lymphotoxin and tumor necrosis factor. Human LTi cells were committed natural killer (NK) cell precursors that produced interleukin 17 (IL-17) and IL-22. In vitro , LTi cells gave rise to RORC + CD127 + NK cells that retained the ability to produce IL-17 and IL-22. Postnatally, similar populations of LTi cell–like cells and RORC + CD127 + NK cells were present in tonsils, and both secreted IL-17 and IL-22 but no interferon-γ. Our data indicate that lymph node organogenesis is controlled by an NK cell precursor population with adaptive immune features and demonstrate a previously unappreciated link between the innate and adaptive immune systems.

The lymphotoxin signalling pathway is best known to immunologists for its crucial roles in promoting the development and the organization of lymphoid organs. However, lymphotoxin also contributes to protective immunity against infection and can regulate the intestinal microbiota. The authors discuss these and the other lesser known immune functions of lymphotoxin. Key Points Lymphotoxin is best known for its roles in promoting lymphoid tissue development, but this cytokine also has other important immunological functions. Lymphotoxin produced by dendritic cells has steady-state immunological functions, including roles in maintaining the cellularity of secondary lymphoid organs and in IgA production. The coordination of the multicellular interactions that contribute to T helper cell and germinal centre responses depends on the lymphotoxin pathway. Antiviral immunity requires the lymphotoxin pathway, both for the regulation of type I interferon production and for innate aspects of the B cell response. Innate lymphoid cells produce lymphotoxin and this promotes interleukin-23 (IL-23)- and IL-22-dependent immune responses at mucosal surfaces. Lymphotoxin production at mucosal surfaces also regulates the microbiota and can contribute to metabolic disease. The lymphotoxin pathway has a crucial role in active immune responses that occur in adult hosts, and a better understanding of these roles may help to guide the development of a new class of therapeutic agents to treat inflammatory diseases. Lymphotoxin (LT) is a member of the tumour necrosis factor (TNF) superfamily that was originally thought to be functionally redundant to TNF, but these proteins were later found to have independent roles in driving lymphoid organogenesis. More recently, LT-mediated signalling has been shown to actively contribute to effector immune responses. LT regulates dendritic cell and CD4 + T cell homeostasis in the steady state and determines the functions of these cells during pathogenic challenges. The LT receptor pathway is essential for controlling pathogens and even contributes to the regulation of the intestinal microbiota, with recent data suggesting that LT-induced changes in the microbiota promote metabolic disease. In this Review, we discuss these newly defined roles for LT, with a particular focus on how the LT receptor pathway regulates innate and adaptive immune responses to microorganisms.

Background The function of Toll-like receptor 2 (TLR2) in host defense against pathogens, especially Mycobacterium tuberculosis (Mtb) is poorly understood. To investigate the role of TLR2 during mycobacterial infection, we analyzed the response of tlr2 zebrafish mutant larvae to infection with Mycobacterium marinum (Mm), a close relative to Mtb, as a model for tuberculosis. We measured infection phenotypes and transcriptome responses using RNA deep sequencing in mutant and control larvae. Results tlr2 mutant embryos at 2 dpf do not show differences in numbers of macrophages and neutrophils compared to control embryos. However, we found substantial changes in gene expression in these mutants, particularly in metabolic pathways, when compared with the heterozygote tlr2 +/− control. At 4 days after Mm infection, the total bacterial burden and the presence of extracellular bacteria were higher in tlr2 −/− larvae than in tlr2 +/− , or tlr2 +/+ larvae, whereas granuloma numbers were reduced, showing a function of Tlr2 in zebrafish host defense. RNAseq analysis of infected tlr2 −/− versus tlr2 +/− shows that the number of up-regulated and down-regulated genes in response to infection was greatly diminished in tlr2 mutants by at least 2 fold and 10 fold, respectively. Analysis of the transcriptome data and qPCR validation shows that Mm infection of tlr2 mutants leads to decreased mRNA levels of genes involved in inflammation and immune responses, including il1b , tnfb , cxcl11aa/ac , fosl1a , and cebpb . Furthermore, RNAseq analyses revealed that the expression of genes for Maf family transcription factors, vitamin D receptors, and Dicps proteins is altered in tlr2 mutants with or without infection. In addition, the data indicate a function of Tlr2 in the control of induction of cytokines and chemokines, such as the CXCR3-CXCL11 signaling axis. Conclusion The transcriptome and infection burden analyses show a function of Tlr2 as a protective factor against mycobacteria. Transcriptome analysis revealed tlr2 -specific pathways involved in Mm infection, which are related to responses to Mtb infection in human macrophages. Considering its dominant function in control of transcriptional processes that govern defense responses and metabolism, the TLR2 protein can be expected to be also of importance for other infectious diseases and interactions with the microbiome.

Little is known about what drives the appearance of lymphoid follicles (LFs), which may function as lymphoid organs in chronic obstructive pulmonary disease (COPD). In animal infection models, pulmonary LF formation requires expression of homeostatic chemokines by stromal cells and dendritic cells, partly via lymphotoxin. To study the role of homeostatic chemokines in LF formation in COPD and to identify mechanism(s) responsible for their production. Peripheral lung homeostatic chemokine and lymphotoxin expression were visualized by immunostainings and quantified by ELISA/quantitative reverse transcriptase-polymerase chain reaction in patients with COPD with and without LFs. Expression of lymphotoxin and homeostatic chemokine receptors was investigated by flow cytometry. Primary lung cell cultures, followed by ELISA/quantitative reverse transcriptase-polymerase chain reaction/flow cytometry, were performed to identify mechanisms of chemokine expression. Polycarbonate membrane filters were used to assess primary lung cell migration toward lung homogenates. LFs expressed the homeostatic chemokine CXCL13. Total CXCL13 levels correlated with LF density. Lung B cells of patients with COPD were important sources of CXCL13 and lymphotoxin and also expressed their receptors. Cigarette smoke extract, H2O2, and LPS exposure up-regulated B cell-derived CXCL13. The LPS-induced increase in CXCL13 was partly mediated via lymphotoxin. Notably, CXCL13 was required for efficient lung B-cell migration toward COPD lung homogenates and induced lung B cells to up-regulate lymphotoxin, which further promoted CXCL13 production, establishing a positive feedback loop. LF formation in COPD may be driven by lung B cells via a CXCL13-dependent mechanism that involves toll-like receptor and lymphotoxin receptor signaling.

BackgroundThe role of tumor necrosis factor (TNF) in the inflammatory response in rheumatoid arthritis (RA) is well established, whereas less is known about the role of TNF’s close homolog, lymphotoxin alpha (LTα).FindingsIncreased levels of LTα are found in the serum and synovial tissue of patients with RA, and in vitro studies found that LTα-induced proliferation of RA fibroblast-like synoviocytes was at a similar level to TNF. These findings support the idea that anti-LTα treatment could be beneficial in patients with RA, but pateclizumab, an anti-LTα antibody, was not as efficacious as the anti-TNF agent adalimumab in reducing symptoms of RA in a head-to-head study, suggesting that anti-LTα therapies might not represent a valid alternative treatment option in patients with RA. However, suppression of LTα activity might be relevant in the context of RA-related comorbidities, as patients with RA have an increased risk of myocardial infarction (MI) compared with the general population, and specific polymorphisms of the LTα gene have been linked to increased MI risk.ConclusionsIn this review, we summarize the key characteristics of LTα and the most recent findings on the role of LTα in RA.