Pretreatment with an antibiotics cocktail enhances the protective effect of probiotics by regulating SCFA metabolism and Th1/Th2/Th17 cell immune responses.

BACKGROUND: Probiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis. RESULTS: The inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells. CONCLUSIONS: Abx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention.

mRNA Vaccines against SARS-CoV-2: Advantages and Caveats.

The application of BNT162b2 and mRNA-1273 vaccines against SARS-CoV-2 infection has constituted a determinant resource to control the COVID-19 pandemic. Since the beginning of 2021, millions of doses have been administered in several countries of North and South America and Europe. Many studies have confirmed the efficacy of these vaccines in a wide range of ages and in vulnerable groups of people against COVID-19. Nevertheless, the emergence and selection of new variants have led to a progressive decay in vaccine efficacy. Pfizer-BioNTech and Moderna developed updated bivalent vaccines-Comirnaty and Spikevax-to improve responses against the SARS-CoV-2 Omicron variants. Frequent booster doses with monovalent or bivalent mRNA vaccines, the emergence of some rare but serious adverse events and the activation of T-helper 17 responses suggest the need for improved mRNA vaccine formulations or the use of other types of vaccines. In this review, we discuss the advantages and limitations of mRNA vaccines targeting SARS-CoV-2 focusing on the most recent, related publications.

Deletion of delta-like 1 homologue accelerates renal inflammation by modulating the Th17 immune response.

Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta-like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1-null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey-1 expression compared to wild-type (WT) littermates. NOTCH1 over-activation in Dlk1-null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL-17A and other related-inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non-canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17-mediated inflammatory response.

GM-CSF is key in the efficacy of vaccine-induced reduction of Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori (H. pylori) colonizes the human gastric mucosa with a high worldwide prevalence. Currently, H. pylori is eradicated by the use of antibiotics. However, elevated antibiotic resistance suggests new therapeutic strategies need to be envisioned: one approach being prophylactic vaccination. Pre-clinical and clinical data show that a urease-based vaccine is efficient in decreasing H. pylori infection through the mobilization of T helper (Th) cells, especially Th17 cells. Th17 cells produce interleukins such as IL-22 and IL-17, among others, and are key players in vaccine efficacy. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing Th17 cells have been identified. AIM: This study explores the possibility that GM-CSF plays a role in the reduction of H. pylori infection following vaccination. RESULTS: We demonstrate that GM-CSF+ IL-17+ Th17 cells accumulate in the stomach mucosa of H. pylori infected mice during the vaccine-induced reduction of H. pylori infection. Secondly, we provide evidence that vaccinated GM-CSF deficient mice only modestly reduce H. pylori infection. Conversely, we observe that an increase in GM-CSF availability reduces H. pylori burden in chronically infected mice. Thirdly, we show that GM-CSF, by acting on gastric epithelial cells, promotes the production of ßdefensin3, which exhibits H. pylori bactericidal activities. CONCLUSION: Taken together, we demonstrate a key role of GM-CSF, most probably originating from Th17 cells, in the vaccine-induced reduction of H. pylori infection.

Novel acute hypersensitivity pneumonitis model induced by airway mycosis and high dose lipopolysaccharide.

BACKGROUND: Inhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice. However, in addition to fungal spores, humans are simultaneously exposed to other inflammatory agents such as lipopolysaccharide (LPS), with uncertain relevance to disease expression. To determine how high dose inhalation of LPS influences the expression of allergic airway disease induced by the allergenic mold Aspergillus niger (A. niger). METHODS: C57BL/6J mice were intranasally challenged with the viable spores of A. niger with and without 1 µg of LPS over two weeks. Changes in airway hyperreactivity, airway and lung inflammatory cell recruitment, antigen-specific immunoglobulins, and histopathology were determined. RESULTS: In comparison to mice challenged only with A. niger, addition of LPS (1 µg) to A. niger abrogated airway hyperresponsiveness and strongly attenuated airway eosinophilia, PAS+ goblet cells and TH2 responses while enhancing TH1 and TH17 cell recruitment to lung. Addition of LPS resulted in more severe, diffuse lung inflammation with scattered, loosely-formed parenchymal granulomas, but failed to alter fungus-induced IgE and IgG antibodies. CONCLUSIONS: In contrast to the strongly allergic lung phenotype induced by fungal spores alone, addition of a relatively high dose of LPS abrogates asthma-like features, replacing them with a phenotype more consistent with acute hypersensitivity pneumonitis (HP). These findings extend the already established link between airway mycosis and asthma to HP and describe a robust model for further dissecting the pathophysiology of HP.

Factors associated with Pneumocystis colonization and circulating genotypes in chronic obstructive pulmonary disease patients with acute exacerbation or at stable state and their homes.

Pneumocystis jirovecii colonization is frequent during chronic obstructive pulmonary disease (COPD) and patients constitute potential contributors to its interhuman circulation. However, the existence of an environmental reservoir cannot be excluded. We assessed the prevalence and factors associated with Pneumocystis colonization during COPD, and studied circulation between patients and their domestic environment. Pneumocystis molecular detection and mtLSU genotyping were performed in oro-pharyngeal washes (OPW) sampled in 58 patients with COPD acute exacerbation, and in indoor dust, sampled in patients' homes using electrostatic dust collectors (EDCs). Lung and systemic inflammation was assessed. Pneumocystis carriage was evaluated in 28 patients after 18 months at stable state. Pneumocystis was detected in 11/58 OPWs during exacerbation (19.0%). Colonized patients presented a significantly lower body mass index, and higher serum IL-17 and CD62P. One patient presented positive detection of typable isolates in both OPW and EDC, with both isolates harboring mtLSU genotype 3. Pneumocystis genotype 1 was further detected in EDCs from three non-colonized patients and one colonized patient with non-typable isolate. Genotypes 1 and 2 were predominant in clinical isolates (both 42%), with genotype 3 representing 16% of isolates. Pneumocystis was detected in 3/28 patients at stable state (10.7%). These data suggest that Pneumocystis colonization could be facilitated by a lower BMI and be related to acute alteration of lung function during COPD exacerbation. It also suggests Th17 pathway and platelet activation could be involved in the anti-Pneumocystis response during colonization. Last, Pneumocystis detection in EDCs supports its potential persistence in indoor dust. LAY SUMMARY: Chronic obstructive pulmonary disease patients tend to be more frequently colonized by Pneumocystis during exacerbation (19.0%) than at stable state (10.7%). Factors associated with colonization include lower BMI, higher IL-17, and CD62P. Pneumocystis detection in patients' dwellings suggests potential persistence in indoor dust.

RNA-Seq analysis of the guppy immune response against Gyrodactylus bullatarudis infection.

Gyrodactylids are ubiquitous ectoparasites of teleost fish, but our understanding of the host immune response against them is fragmentary. Here, we used RNA-Seq to investigate genes involved in the primary response to infection with Gyrodactylus bullatarudis on the skin of guppies, Poecilia reticulata, an important evolutionary model, but also one of the most common fish in the global ornamental trade. Analysis of differentially expressed genes identified several immune-related categories, including IL-17 signalling pathway and Th17 cell differentiation, cytokine-cytokine receptor interaction, chemokine signalling pathway, NOD-like receptor signalling pathway, natural killer cell-mediated cytotoxicity and pathways involved in antigen recognition, processing and presentation. Components of both the innate and the adaptive immune responses play a role in response to gyrodactylid infection. Genes involved in IL-17/Th17 response were particularly enriched among differentially expressed genes, suggesting a significant role for this pathway in fish responses to ectoparasites. Our results revealed a sizable list of genes potentially involved in the teleost-gyrodactylid immune response.

Differential Expression of SMAD Genes and S1PR1 on Circulating CD4+ T Cells in Multiple Sclerosis and Crohn's Disease.

The Th17 immune response plays a key role in autoimmune diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Expression of Th17-related genes in inflamed tissues has been reported in autoimmune diseases. However, values are frequently obtained using invasive methods. We aimed to identify biomarkers of MS in an accessible sample, such as blood, by quantifying the relative expression of 91 Th17-related genes in CD4+ T lymphocytes from patients with MS during a relapse or during a remitting phase. We also compared our findings with those of healthy controls. After confirmation in a validation cohort, expression of SMAD7 and S1PR1 mRNAs was decreased in remitting disease (-2.3-fold and -1.3-fold, respectively) and relapsing disease (-2.2-fold and -1.3-fold, respectively). No differential expression was observed for other SMAD7-related genes, namely, SMAD2, SMAD3, and SMAD4. Under-regulation of SMAD7 and S1PR1 was also observed in another autoimmune disease, Crohn's disease (CD) (-4.6-fold, -1.6-fold, respectively), suggesting the presence of common markers for autoimmune diseases. In addition, expression of TNF, SMAD2, SMAD3, and SMAD4 were also decreased in CD (-2.2-fold, -1.4-fold, -1.6-fold, and -1.6-fold, respectively). Our study suggests that expression of SMAD7 and S1PR1 mRNA in blood samples are markers for MS and CD, and TNF, SMAD2, SMAD3, and SMAD4 for CD. These genes could prove useful as markers of autoimmune diseases, thus obviating the need for invasive methods.

A single administration of human adipose tissue-derived mesenchymal stromal cells (MSC) induces durable and sustained long-term regulation of inflammatory response in experimental colitis.

Current therapies for inflammatory bowel diseases (IBD) are aimed at controlling the exacerbated response in the gut, but no treatment is fully effective for many refractory patients. Mesenchymal stromal cells (MSC) are multi-potent cells with regulatory immunosuppressive activity that may control inflammatory diseases. In this study, we investigated the short- and especially the long-term protective effects of MSC on experimental colitis. We show that MSC elicited protection to acute intestinal inflammation with gain of weight, improvement in the clinical disease score and expressive reduction in the mortality rate of treated mice. MSC changed the population of neutrophils, eosinophils and augmented the frequency of CD4 T lymphocytes in the gut-draining lymph nodes, together with reduced accumulation of these cells in the colon intraepithelial compartment. Interestingly, there were increased levels of programmed death 1 (PD-1) and glucocorticoid-induced tumour necrosis factor receptor family-related receptor (GITR) in the spleen regulatory T cells of mice that received MSC treatment, which also presented a reversal in the pattern of immune response in the gut, with diminished inflammatory, T helper type 1 (Th1) and Th17 profile, in contrast to augmented Th2 responses. Most strikingly, this balanced response elicited by a single administration of MSC during the acute colitis persisted long-term, with restored goblet cells, eosinophils and maintenance of elevated gut interleukin (IL)-4, besides increased CD4+ CD25+ PD-1+ cells in the spleen and reduced Th17 response in mesenteric lymph nodes (MLN) of treated mice on day 60. Taken together, our findings provided a significant contribution to translational immunology by pointing human adipose tissue-derived MSC as a novel therapeutic approach with long-term beneficial regulatory effects in experimental colitis.

Effect of injected dexamethasone on relative cytokine mRNA expression in bronchoalveolar lavage fluid in horses with mild asthma.

BACKGROUND: Mild equine asthma is a common inflammatory airway disease of the horse. The primary treatment of mild equine asthma is corticosteroids. The purpose of this study was to investigate the effects of injected dexamethasone on relative IL-1ß, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p35, IL-17, IL-23, IFN-γ, Eotaxin-2 and TNF-α mRNA expression in bronchoalveolar lavage (BAL) fluid in healthy Thoroughbred horses (n = 6), and those with mild equine asthma (n = 7). RESULTS: Horses with mild equine asthma had a significantly greater bronchoalveolar lavage mast cell percentage than healthy horses both before and after treatment. Mild equine asthma was associated with a 4.95-fold up-regulation of IL-17 (p = 0.026) and a 2.54-fold down-regulation of IL-10 (p = 0.049) compared to healthy horses. TNF-α was down-regulated in response to dexamethasone treatment in both healthy horses (3.03-fold, p = 0.023) and those with mild equine asthma (1.75-fold, p = 0.023). IL-5 was also down-regulated in horses with mild asthma (2.17-fold, p = 0.048). CONCLUSIONS: Horses with mild equine asthma have a lower concentration of IL-10 in BAL fluid than healthy controls which concurs with human asthmatics. The marked up-regulation of IL-17 in horses with mild asthma suggests these horses had a true tendency of "allergic" airway inflammation in response to environmental allergens. Dexamethasone administration exerted anti-inflammatory effects associated with down-regulation of TNF-α in all horses, and decreased levels of IL-5 mRNA expression in horses with mild equine asthma. The inhibition of the Th-2 response, without any alterations to the airway cytology, indicates that maintained exposure to environmental allergens perpetuates airway inflammation.

IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation.

The IL-17 cytokine family and the cognate receptors thereof have a unique role in organ-specific autoimmunity. Most studies have focused on the founding member of the IL-17 family, IL-17A, as the central mediator of diseases. Indeed, although pathogenic functions have been ascribed to IL-17A and IL-17F in the context of immune-mediated glomerular diseases, the specific functions of the other IL-17 family members in immunity and inflammatory kidney diseases is largely unknown. Here, we report that compared with healthy controls, patients with acute Anti-neutrophil cytoplasmatic antibody (ANCA)-associated crescentic glomerulonephritis (GN) had significantly elevated serum levels of IL-17C (but not IL-17A, F, or E). In mouse models of crescentic GN (nephrotoxic nephritis) and pristane-induced lupus nephritis, deficiency in IL-17C significantly ameliorated the course of GN in terms of renal tissue injury and kidney function. Deficiency of the unique IL-17C receptor IL-17 receptor E (IL-17RE) provided similar protection against crescentic GN. These protective effects associated with a reduced TH17 response. Bone marrow transplantation experiments revealed that IL-17C is produced by tissue-resident cells, but not by lymphocytes. Finally, IL-17RE was highly expressed by CD4+ TH17 cells, and loss of this expression prevented the TH17 responses and subsequent tissue injury in crescentic GN. Our findings indicate that IL-17C promotes TH17 cell responses and immune-mediated kidney disease via IL-17RE expressed on CD4+ TH17 cells. Targeting the IL-17C/IL-17RE pathway may present an intriguing therapeutic strategy for TH17-induced autoimmune disorders.

Glucan-Chitin Particles Enhance Th17 Response and Improve Protective Efficacy of a Multivalent Antigen (rCpa1) against Pulmonary Coccidioides posadasii Infection.

Developing an effective and safe recombinant vaccine requires microbe-specific antigens combined with an adjuvant/delivery system to strengthen protective immunity. In this study, we designed and expressed a multivalent recombinant Coccidioides polypeptide antigen (rCpa1) that consists of three previously identified antigens (i.e., Ag2/Pra, Cs-Ag, and Pmp1) and five pathogen-derived peptides with high affinity for human major histocompatibility complex class II (MHC-II) molecules. The purified rCpa1 was encapsulated into four types of yeast cell wall particles containing ß-glucan, mannan, and chitin in various proportions or was mixed with an oligonucleotide (ODN) containing two methylated dinucleotide CpG motifs. This multivalent antigen encapsulated into glucan-chitin particles (GCP-rCpa1) showed significantly greater reduction of fungal burden for human HLA-DR4 transgenic mice than the other adjuvant-rCpa1 formulations tested. Among the adjuvants tested, both GCPs and ß-glucan particles (GPs) were capable of stimulating a mixed Th1 and Th17 response. Mice vaccinated with GCP-rCpa1 showed higher levels of interleukin 17 (IL-17) production in T-cell recall assays and earlier lung infiltration by activated Th1 and Th17 cells than GP-rCpa1-vaccinated mice. Both C57BL/6 and HLA-DR4 transgenic mice that were vaccinated with the GCP-rCpa1 vaccine showed higher survival rates than mice that received GCPs alone. Concurrently, the GCP-rCpa1 vaccine stimulated greater infiltration of the injection sites by macrophages, which engulf and process the vaccine for antigen presentation, than the GP-rCpa1 vaccine. This is the first attempt to systematically characterize the presentation of a multivalent coccidioidomycosis vaccine encapsulated with selected adjuvants that enhance the protective cellular immune response to infection.

Mucosal associated invariant T cells from human breast ducts mediate a Th17-skewed response to bacterially exposed breast carcinoma cells.

BACKGROUND: Antimicrobial T cells play key roles in the disease progression of cancers arising in mucosal epithelial tissues, such as the colon. However, little is known about microbe-reactive T cells within human breast ducts and whether these impact breast carcinogenesis. METHODS: Epithelial ducts were isolated from primary human breast tissue samples, and the associated T lymphocytes were characterized using flow cytometric analysis. Functional assays were performed to determine T-cell cytokine secretion in response to bacterially treated human breast carcinoma cells. RESULTS: We show that human breast epithelial ducts contain mucosal associated invariant T (MAIT) cells, an innate T-cell population that recognizes specific bacterial metabolites presented by nonclassical MR1 antigen-presenting molecules. The MAIT cell population from breast ducts resembled that of peripheral blood in its innate lymphocyte phenotype (i.e., CD161, PLZF, and interleukin [IL]-18 receptor coexpression), but the breast duct MAIT cell population had a distinct T-cell receptor Vß use profile and was markedly enriched for IL-17-producing cells compared with blood MAIT cells. Breast carcinoma cells that had been exposed to Escherichia coli activated MAIT cells in an MR1-dependent manner. However, whereas phorbol 12-myristate 13-acetate/ionomycin stimulation induced the production of both interferon-γ and IL-17 by breast duct MAIT cells, bacterially exposed breast carcinoma cells elicited a strongly IL-17-biased response. Breast carcinoma cells also showed upregulated expression of natural killer group 2 member D (NKG2D) ligands compared with primary breast epithelial cells, and the NKG2D receptor contributed to MAIT cell activation by the carcinoma cells. CONCLUSIONS: These results demonstrate that MAIT cells from human breast ducts mediate a selective T-helper 17 cell response to human breast carcinoma cells that were exposed to E. coli. Thus, cues from the breast microbiome and the expression of stress-associated ligands by neoplastic breast duct epithelial cells may shape MAIT cell responses during breast carcinogenesis.

Immune Profiling of T Cells Infiltrating Vitreous Humor in Tubercular Uveitis.

PURPOSE: To assess cellular composition and local cytokine response in vitreous humor of tubercular uveitis. METHODS: Cells were collected from vitreous cassettes and peripheral blood of 8 tubercular uveitis and 5 control subjects, undergoing vitrectomy and analyzed by flow cytometry for cellular composition, activation status, proinflammatory cytokine expression, and uptake of TLR9 ligand, CpG ODN 2216. RESULTS: CD3 + T cells with equal proportion of CD4+ and CD8 + T cells formed major fraction of infiltrating cells. The vitreous humor showed higher expression of recent activation marker, CD69, and proinflammatory cytokines, IFN-γ and IL-17A, in CD4 + T cells as compared to peripheral blood. Lastly, intraocular CD4 + T cells showed reduced uptake of ODN 2216 than peripheral blood. CONCLUSIONS: Our results indicate that local antigenic stimuli trigger T cell infiltration and activation of CD4 + T cells that are hyporesponsive to TLR9 stimulation. These infiltrating T cells might be responsible in further aggravating ocular inflammation.

Differential control of CD4(+) T-cell subsets by the PD-1/PD-L1 axis in a mouse model of allergic asthma.

Studies examining the role of PD-1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we demonstrate that blockade of PD-1/PD-L1 has distinct influences on different CD4(+) T-cell subsets. PD-1/PD-L1 blockade enhances airway hyperreactivity (AHR), not by altering the magnitude of the underlying Th2-type immune response, but by allowing the development of a concomitant Th17-type immune response. Supporting differential CD4(+) T-cell responsiveness to PD-1-mediated inhibition, naïve PD-1(-/-) mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD-1 in WT cells limited cytokine production by in vitro polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro polarized Th2 cells. Furthermore, PD-1 ligation enhanced Th2 cytokine production by naïve T cells cultured under nonpolarizing conditions. These data demonstrate that different CD4(+) T-cell subsets respond differentially to PD-1 ligation and may explain some of the variable results observed in control of allergic asthma by the PD-1 family members. As the PD-1/PD-L1 axis limits asthma severity by constraining Th17 cell activity, this suggests that severe allergic asthma may be associated with a defective PD-1/PD-L1 regulatory axis in some individuals.

Mycobacterium tuberculosis PstS1 amplifies IFN-γ and induces IL-17/IL-22 responses by unrelated memory CD4+ T cells via dendritic cell activation.

The immunological mechanisms that modulate protection during Mycobacterium tuberculosis (Mtb) infection or vaccination are not fully understood. Secretion of IFN-γ and, to a lesser extent, of IL-17 by CD4(+) T cells plays a major role both in protection and immunopathology. Few Mtb Ags interacting with DCs affect priming, activation, and regulation of Ag-unrelated CD4(+) T-cell responses. Here we demonstrate that PstS1, a 38 kDa-lipoprotein of Mtb, promotes Ag-independent activation of memory T lymphocytes specific for Ag85B or Ag85A, two immunodominant protective Ags of Mtb. PstS1 expands CD4(+) and CD8(+) memory T cells, amplifies secretion of IFN-γ and IL-22 and induces IL-17 production by effector memory cells in an Ag-unrelated manner in vitro and in vivo. These effects were mediated through the stimulation of DCs, particularly of the CD8α(-) subtype, which respond to PstS1 by undergoing phenotypic maturation and by secreting IL-6, IL-1ß and, to a lower extent, IL-23. IL-6 secretion by PstS1-stimulated DCs was required for IFN-γ, and to a lesser extent for IL-22 responses by Ag85B-specific memory T cells. These results may open new perspectives for immunotherapeutic strategies to control Th1/Th17 immune responses in Mtb infections and in vaccinations against tuberculosis.

TLR ligand ligation switches adenosine receptor usage of BMDCs leading to augmented Th17 responses in experimental autoimmune uveitis.

The extracellular level of adenosine increases greatly during inflammation, which modulates immune responses. We have previously reported that adenosine enhances Th17 responses while it suppresses Th1 responses. This study examined whether response of DC to adenosine contributes to the biased effect of adenosine and determined whether adenosine and TLR ligands have counteractive or synergistic effects on DC function. Our results show that adenosine is actively involved in both in vitro and in vivo activation of pathogenic T cells by DCs; however, under adenosine effect DCs' capability of promoting Th1 versus Th17 responses are dissociated. Moreover, activation of A2ARs on DCs inhibits Th1 responses whereas activation of A2BRs on DC enhances Th17 responses. An intriguing observation was that TLR engagement switches the adenosine receptor from A2ARs to A2BRs usage of bone marrow-derived dendritic cells (BMDCs) and adenosine binding to BMDCs via A2BR converts adenosine's anti-to proinflammatory effect. The dual effects of adenosine and TLR ligand on BMDCs synergistically enhances the Th17 responses whereas the dual effect on Th1 responses is antagonistic. The results imply that Th17 responses will gain dominance when inflammatory environment accumulates both TLR ligands and adenosine and the underlying mechanisms include that TLR ligand exposure has a unique effect switching adenosine receptor usage of DCs from A2ARs to A2BRs, via which Th17 responses are promoted. Our observation should improve our understanding on the balance of Th1 and Th17 responses in the pathogenesis of autoimmune and other related diseases.

Prenatal antibiotics exposure does not influence experimental allergic asthma in mice.

Changes in microbiome (dysbiosis) contribute to severity of allergic asthma. Preexisting epidemiological studies in humans correlate perinatal dysbiosis with increased long-term asthma severity. However, these studies cannot discriminate between prenatal and postnatal effects of dysbiosis and suffer from a high variability of dysbiotic causes ranging from antibiotic treatment, delivery by caesarian section to early-life breastfeeding practices. Given that maternal antibiotic exposure in mice increases the risk of newborn bacterial pneumonia in offspring, we hypothesized that prenatal maternal antibiotic-induced dysbiosis induces long-term immunological effects in the offspring that also increase long-term asthma severity. Therefore, dams were exposed to antibiotics (gentamycin, ampicillin, vancomycin) from embryonic day 15 until birth. Six weeks later, asthma was induced in the offspring by repeated applications of house dust mite extract. Airway function, cytokine production, pulmonary cell composition and distribution were assessed. Our study revealed that prenatally induced dysbiosis in mice led to an increase in pulmonary Th17+ non-conventional T cells with limited functional effect on airway resistance, pro-asthmatic Th2/Th17 cytokine production, pulmonary localization and cell-cell contacts. These data indicate that dysbiosis-related immune-modulation with long-term effects on asthma development occurs to a lesser extent prenatally and will allow to focus future studies on more decisive postnatal timeframes.

Helicobacter pylori infection: How does age influence the inflammatory pattern?

The inflammatory pattern during Helicobacter pylori (H. pylori) infection is changeable and complex. During childhood, it is possible to observe a predominantly regulatory response, evidenced by high concentrations of key cytokines for the maintenance of Treg responses such as TGF-ß1 and IL-10, in addition to high expression of the transcription factor FOXP3. On the other hand, there is a predominance of cytokines associated with the Th1 and Th17 responses among H. pylori-positive adults. In the last few years, the participation of the Th17 response in the gastric inflammation against H. pylori infection has been highlighted due to the high levels of TGF-ß1 and IL-17 found in this infectious scenario, and growing evidence has supported a close relationship between this immune response profile and unfavorable outcomes related to the infection. Moreover, this cytokine profile might play a pivotal role in the effectiveness of anti-H. pylori vaccines. It is evident that age is one of the main factors influencing the gastric inflammatory pattern during the infection with H. pylori, and understanding the immune response against the bacterium can assist in the development of alternative prophylactic and therapeutic strategies against the infection as well as in the comprehension of the pathogenesis of the outcomes related to that microorganism.