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Key Points Interferons (IFNs) are widely expressed cytokines with strong antiviral properties. There are three main types of IFNs: type I IFNs, type II IFN and type III IFNs. In addition to their role in response to viruses, type I IFNs (mainly IFNα and IFNβ) are induced by bacterial infections. The production of type I IFNs in response to bacterial ligands is mediated through Toll-like receptor (TLR)-dependent and -independent mechanisms. TLR3, TLR4, TLR7 and TLR9 have been linked to the production of type I IFNs. The TLR-independent pathways involve the cytoplasmic nucleic acid sensors retinoic-acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), stimulator of interferon genes (STING) and DNA-dependent activator of IRFs (DAI). Type I IFNs activate several Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling pathways, which regulate the transcription of target genes. In addition to the classical JAK–STAT signalling pathways, type I IFNs activate other signalling cascades. Type I IFNs mediate the regulatory functions of dendritic cells in the gut and the protective effect of TLR ligands in colonic injury. Activation of type I IFN signalling has an important role in T helper cell differentiation and in the suppressive function of regulatory T cells. Type I IFNs both negatively and positively regulate the activation of different types of inflammasome complex and the production of interleukin-1β. In addition to their role as antiviral cytokines, type I IFNs have a wide range of immunomodulatory effects in response to bacterial infections. Type I IFNs are implicated in different autoimmune and inflammatory conditions, although their role in each condition varies. Some autoimmune diseases are improved by the biological effects of type I IFNs, whereas others benefit from type I IFN inhibition. Type I interferons (IFNs) have become synonymous with antiviral immunity. But, as discussed in this Review, type I IFNs also have roles in bacterial infections, in intestinal homeostasis and in inflammatory and autoimmune diseases. Interferon-α (IFNα) and IFNβ, collectively known as type I IFNs, are the major effector cytokines of the host immune response against viral infections. However, the production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed. The main focus of this Review is the underappreciated immunomodulatory functions of type I IFNs in health and disease. We discuss their function in the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis and inflammatory and autoimmune diseases.

Failure of gut homeostasis is an important factor in the pathogenesis and progression of systemic inflammation, which can culminate in multiple organ failure and fatality. Pathogenic events in critically ill patients include mesenteric hypoperfusion, dysregulation of gut motility, and failure of the gut barrier with resultant translocation of luminal substrates. This is followed by the exacerbation of local and systemic immune responses. All these events can contribute to pathogenic crosstalk between the gut, circulating cells, and other organs like the liver, pancreas, and lungs. Here we review recent insights into the identity of the cellular and biochemical players from the gut that have key roles in the pathogenic turn of events in these organ systems that derange the systemic inflammatory homeostasis. In particular, we discuss the dangers from within the gastrointestinal tract, including metabolic products from the liver (bile acids), digestive enzymes produced by the pancreas, and inflammatory components of the mesenteric lymph.

[...]Zuazo et al.argue that targeting systemic CD4 immunity might be an important element of PD1-based therapies and propose that pre-treatment levels of specific CD4+ T cell memory subsets in the periphery are correlated with response in NSCLC. Of note, Hdac9 is induced by Mef2d as part of a negative feedback loop (6). [...]Di Giorgio et al.propose a mechanism whereby two members of the Mef2 family, Mef2c and Mef2d, coordinate to turn the expression of Hdac9 on and off and support Treg immune suppressive functions. [...]the papers included in this Research Topic highlight the distinct contribution of different CD4+ T cell populations to cancer immune surveillance and immunotherapy.

Absent in melanoma 2 (AIM2) is a cytosolic receptor that recognizes double-stranded DNA (dsDNA) and triggers the activation of the inflammasome cascade. Activation of the inflammasome results in the maturation of inflammatory cytokines, such as interleukin (IL)-1 β and IL-18, and a form of cell death known as pyroptosis. Owing to the conserved nature of its ligand, AIM2 is important during immune recognition of multiple pathogens. Additionally, AIM2 is also capable of recognizing host DNA during cellular damage or stress, thereby contributing to sterile inflammatory diseases. Inflammation, either in response to pathogens or due to sterile cellular damage, is at the center of the most prevalent and life-threatening liver diseases. Therefore, during the last 15 years, the study of inflammasome activation in the liver has emerged as a new research area in hepatology. Here, we discuss the known functions of AIM2 in the pathogenesis of different hepatic diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), hepatitis B, liver fibrosis, and hepatocellular carcinoma (HCC).

Objective The aetiology of Crohn's disease (CD) has been related to nucleotide-binding oligomerisation domain containing 2 (NOD2) and ATG16L1 gene variants. The observation of bacterial DNA translocation in patients with CD led us to hypothesise that this process may be facilitated in patients with NOD2/ATG16L1-variant genotypes, affecting the efficacy of anti-tumour necrosis factor (TNF) therapies. Design 179 patients with Crohn's disease were included. CD-related NOD2 and ATG16L1 variants were genotyped. Phagocytic and bactericidal activities were evaluated in blood neutrophils. Bacterial DNA, TNFα, IFNγ, IL-12p40, free serum infliximab/adalimumab levels and antidrug antibodies were measured. Results Bacterial DNA was found in 44% of patients with active disease versus 23% of patients with remitting disease (p=0.01). A NOD2-variant or ATG16L1-variant genotype was associated with bacterial DNA presence (OR 4.8; 95% CI 1.1 to 13.2; p=0.001; and OR 2.4; 95% CI 1.4 to 4.7; p=0.01, respectively). This OR was 12.6 (95% CI 4.2 to 37.8; p=0.001) for patients with a double-variant genotype. Bacterial DNA was associated with disease activity (OR 2.6; 95% CI 1.3 to 5.4; p=0.005). Single and double-gene variants were not associated with disease activity (p=0.19). Patients with a NOD2-variant genotype showed decreased phagocytic and bactericidal activities in blood neutrophils, increased TNFα levels in response to bacterial DNA and decreased trough levels of free anti-TNFα. The proportion of patients on an intensified biological therapy was significantly higher in the NOD2-variant groups. Conclusions Our results characterise a subgroup of patients with CD who may require a more aggressive therapy to reduce the extent of inflammation and the risk of relapse.

Background Individuals with certain chronic inflammatory lung diseases have a higher risk of developing lung cancer (LC). However, the underlying mechanisms remain largely unknown. Here, we hypothesized that chronic exposure to house dust mites (HDM), a common indoor aeroallergen associated with the development of asthma, accelerates LC development through the induction of chronic lung inflammation (CLI).  Methods The effects of HDM and heat-inactivated HDM (HI-HDM) extracts were evaluated in two preclinical mouse models of LC (a chemically-induced model using the carcinogen urethane and a genetically-driven model with oncogenic Kras G12D activation in lung epithelial cells) and on murine macrophages in vitro . Pharmacological blockade or genetic deletion of the Nod-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, caspase-1, interleukin-1β (IL-1β), and C–C motif chemokine ligand 2 (CCL2) or treatment with an inhaled corticosteroid (ICS) was used to uncover the pro-tumorigenic effect of HDM.  Results Chronic intranasal (i.n) instillation of HDM accelerated LC development in the two mouse models. Mechanistically, HDM caused a particular subtype of CLI, in which the NLRP3/IL-1β signaling pathway is chronically activated in macrophages, and made the lung microenvironment conducive to tumor development. The tumor-promoting effect of HDM was significantly decreased by heat treatment of the HDM extract and was inhibited by NLRP3, IL-1β, and CCL2 neutralization, or ICS treatment. Conclusions Collectively, these data indicate that long-term exposure to HDM can accelerate lung tumorigenesis in susceptible hosts (e.g., mice and potentially humans exposed to lung carcinogens or genetically predisposed to develop LC).

Cyclic AMP (cAMP) is involved in many biological processes but little is known regarding its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent mechanism) regulates conventional type-2 Dendritic Cells (cDC2s) in mice and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors essential for cDC2-mediated Th2 induction. In mice, genetic loss of IRF4 phenocopies the effects of cAMP on Th17 induction and restoration of IRF4 prevents the cAMP effect. Moreover, curdlan, a PRR-dependent microbial product, activates CREB and represses IRF4 and KLF4, resulting in a pro-Th17 phenotype of cDC2s. These in vitro and in vivo results define a novel signaling pathway by which cDC2s display plasticity and provide a new molecular basis for the classification of novel cDC2 and cDC17 subsets. The findings also reveal that repressing IRF4 and KLF4 pathway can be harnessed for immuno-regulation.

BACKGROUND: Intestinal homeostasis plays an important role in bacteria-derived complications in cirrhosis. Intestinal lymphocytes are responsible for immune effector functions and can be modulated by certain probiotics. We evaluate the interaction between Bifidobacterium pseudocatenulatum CECT7765 and intestinal lymphocytes in mice with cirrhosis. ANIMALS AND METHODS: Cirrhosis was induced by intragastrical administration of carbon tetrachloride in Balb/C mice. One week prior to laparotomy, animals received B. pseudocatenulatum CECT7765 (10⁷, 10⁹ or 10¹⁰ cfu/daily) or placebo. Chemokine receptor and cytokine expression were evaluated in intestinal lymphocytes. Gut permeability was studied by FITC-LPS recovery in vivo. Luminal antigens, inflammation and functional markers were evaluated in liver samples. RESULTS: Bifidobacterium pseudocatenulatum CECT7765 decreased the expression of pro-inflammatory chemokine receptors CCR6, CCR9, CXCR3 and CXCR6 in intestinal lymphocytes from cirrhotic mice in a concentration-dependent manner. The bifidobacterial strain induced a shift towards an anti-inflammatory cytokine profile in this cell subset. B. pseudocatenulatum CECT7765-induced inflammatory modulation was TLR2-mediated, as in vitro TLR2 blockade inhibited the reduction of TNF-alpha and its receptors and the increase of IL-10 and IL-10 receptor secretion. The recovery rate of administered fluorescence-labelled endotoxin was significantly and dose-dependently lowered with the bifidobacterial strain. The reduced intestinal permeability was associated with a decreased burden of bacterial antigens in the liver of mice treated with B. pseudocatenulatum CECT7765. Liver function and inflammation were improved with the use of the bifidobacterial strain at the highest dose tested (10¹⁰ cfu). CONCLUSION: Bifidobacterium pseudocatenulatum CECT7765 improves gut homeostasis and prevents gut-derived complications in experimental chronic liver disease.

Absent in melanoma 2 (AIM2) is a cytosolic dsDNA sensor that has been broadly studied for its role in inflammasome assembly. However, little is known about the function of AIM2 in adaptive immune cells. The purpose of this study was to investigate whether AIM2 has a cell-intrinsic role in CD4+ T cell differentiation or function. We found that AIM2 is expressed in both human and mouse CD4+ T cells and that its expression is affected by T cell receptor (TCR) activation. Naïve CD4+ T cells from AIM2-deficient (Aim2−/−) mice showed higher ability to maintain forkhead box P3 (FOXP3) expression in vitro, while their capacity to differentiate into T helper (Th)1, Th2 or Th17 cells remained unaltered. Transcriptional profiling by RNA sequencing showed that AIM2 might affect regulatory T cell (Treg) stability not by controlling the expression of Treg signature genes, but through the regulation of the cell’s metabolism. In addition, in a T cell transfer model of colitis, Aim2−/−-naïve T cells induced less severe body weight loss and displayed a higher ability to differentiate into FOXP3+ cells in vivo. In conclusion, we show that AIM2 function is not confined to innate immune cells but is also important in CD4+ T cells. Our data identify AIM2 as a regulator of FOXP3+ Treg cell differentiation and as a potential intervention target for restoring T cell homeostasis.

During the last decade, immune checkpoint inhibition (ICI) has become a pillar of cancer therapy. Antibodies targeting CTLA-4 or PD-1/PD-L1 have been approved in several malignancies, with thousands of clinical trials currently underway. While the majority of cancer immunotherapies have traditionally focused on enhancing cytotoxic responses by CD8 + or NK cells, there are clear evidences that CD4 + T cell responses can modulate the immune response against tumors and influence the efficacy of ICI therapy. CD4 + T cells can differentiate into several subsets of helper T cells (Th) or regulatory T cells (Treg), with a wide range of effector and/or regulatory functions. Importantly, different Th subsets may have different and sometimes contrasting roles in the clinical response to ICI therapy, which in addition may vary depending on the organ and tumor niche. In this review, we discuss recent evidence that highlights how ICI therapy impacts Th1, Th9, and Th17 cells and vice versa . These data might be important designing better interventions that unleash the full potential of immune response against cancer.