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Lactoperoxidase (1.11.1.7, LPO) is a mammalian heme peroxidase found in the extracellular fluids of mammals including plasma, saliva, airway epithelial lining fluids, nasal lining fluid, milk, tears, gastric juices, and intestinal mucosa. To perform its innate immune action against invading microbes, LPO utilizes hydrogen peroxide (H2O2) to convert thiocyanate (SCN−) and iodide (I−) ions into the oxidizing compounds hypothiocyanite (OSCN−) and hypoiodite (IO−). Previously determined structures of the complexes of LPO with SCN−, OSCN−, and I− show that SCN− and I− occupy appropriate positions in the distal heme cavity as substrates while OSCN− binds in the distal heme cavity as a product inhibitor. We report here the structure of the complex of LPO with IO− as the first structural evidence of the conversion of iodide into hypoiodite by LPO. To obtain this complex, a solution of LPO was first incubated with H2O2, then mixed with ammonium iodide solution and the complex crystallized by the addition of PEG‐3350, 20% (wt/vol). These crystals were used for X‐ray intensity data collection and structure analysis. The structure determination revealed the presence of four hypoiodite ions in the substrate binding channel of LPO. In addition to these, six other hypoiodite ions were observed at different exterior sites. We surmise that the presence of hypoiodite ions in the distal heme cavity blocks the substrate binding site and inhibits catalysis. This was confirmed by activity experiments with the colorimetric substrate, ABTS (2,2′‐azino‐bis(3‐ethylbenzthiazoline‐sulfonic acid)), in the presence of hypoiodite and iodide ions. PDB Code(s): 7VE3; [ABSTRACT FROM AUTHOR]

Among CD4+ T-cells, T helper 17 (Th17) cells play a sentinel role in the defense against bacterial/fungal pathogens at mucosal barriers. However, Th17 cells are also highly susceptible to HIV-1 infection and are rapidly depleted from gut mucosal sites, causing an imbalance of the Th17/Treg ratio and impairing cytokines production. Consequently, damage to the gut mucosal barrier leads to an enhanced microbial translocation and systemic inflammation, a hallmark of HIV-1 disease progression. Th17 cells’ expression of mucosal homing receptors (CCR6 and α4β7), as well as HIV receptors and co-receptors (CD4, α4β7, CCR5, and CXCR4), contributes to susceptibility to HIV infection. The up-regulation of numerous intracellular factors facilitating HIV production, alongside the downregulation of factors inhibiting HIV, helps to explain the frequency of HIV DNA within Th17 cells. Th17 cells harbor long-lived viral reservoirs in people living with HIV (PLWH) receiving antiretroviral therapy (ART). Moreover, cell longevity and the proliferation of a fraction of Th17 CD4 T cells allow HIV reservoirs to be maintained in ART patients.

The risk of HIV acquisition is low on a per-contact basis but increased by transmission co-factors such as other sexually transmitted infections (STIs). Human papillomavirus (HPV) is a prevalent STI that most individuals will acquire HPV in their lifetime. Current HPV vaccines can prevent newly acquired infections, but are largely ineffective against established HPV, complicating worldwide eradication efforts. In addition to being the causative agent of cervical cancer, accumulating evidence suggests that HPV infection and/or accompanying cervical inflammation increase the risk of HIV infection in men and women. The fact that immunological features observed during HPV infection overlap with cellular and molecular pathways known to enhance HIV susceptibility underscore the potential interplay between these two viral infections that fuel their mutual spread. Here we review current insights into how HPV infection and the generation of anti-HPV immunity contribute to higher HIV transmission rates, and the impact of HPV on mucosal inflammation, immune cell trafficking, and epithelial barrier function.

Interactions between parasites during co‐infections are often complex and can impact immunization and treatment programmes, as well as disease outcomes and morbidity. However, little is known about these interactions and the mechanisms involved. In this study, a coproparasitological survey was carried out in school‐age children living in endemic areas of parasitic infection in the state of Sergipe, Northeastern Brazil. Anti‐helminth‐specific and total secretory immunoglobulin‐A (SIgA) levels were measured in stool and saliva samples and were compared in children presenting monoparasitism, polyparasitism (helminths and/or intestinal protozoa) and no infections. The survey showed that protozoa were more prevalent than helminths, and that there was a high frequency of polyparasitism in the studied population, mainly from combinations of protozoan species. Although less frequent, combinations between species of protozoa and helminths were also observed. The levels of salivary SIgA in these co‐infected individuals were lower than the average observed in infections with helminths alone. Although the children participating in this survey were asymptomatic, and it was, therefore, not possible to evaluate the impact of salivary SIgA reduction on the diseases, and the study highlights the need for further investigations of co‐infections by intestinal parasites and the effects on immune response induced by the interactions between different parasites. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Background: HIV-infected immunological nonresponders (INRs) have increased risk of non-AIDS morbidity and compromised gut barrier immunity. Probiotics are widely used to improve health. We assessed the effects of probiotics in INRs with a comprehensive analysis of gut immunity and microbiome in terminal ileum and sigmoid colon. Methods: The study involved clinical intervention with five-strain probiotic capsules (1.2 × 1010 CFUs/d) for 8 weeks in 20 INRs with CD4+ T-cell counts <400 cells/µL and plasma HIV RNA <50 copies/mL for more than 3.5 years. Colonoscopy with sampling of gut biopsies from terminal ileum and sigmoid colon and fecal and blood sampling were performed before and after the intervention. Flow cytometry (cytokine production, immune activation, and exhaustion), ELISA (inflammation, microbial translocation, and enterocyte damage), and 16S rRNA sequencing analyses were applied. Results: In the terminal ileum, increased alpha diversity, increased abundance of Bifidobacterium sp., and decreased frequencies of IL-22+ CD4+ T cells were observed. The increased abundance of Bifidobacterium sp. in the terminal ileum correlated with increased fraction of CD4+ T cells in the same compartment (r = 0.54, P = 0.05) and increased CD4/CD8 ratio in peripheral blood (r = 0.49, P = 0.05). There were no corresponding changes in the sigmoid colon and no changes in fecal microbiome. Probiotic intervention did not affect peripheral blood CD4 count, viral load, or soluble markers of inflammation and microbial translocation. Conclusions: Probiotics induced segment-specific changes in the terminal ileum but did not affect systemic CD4 counts in INRs. Further clinical studies are warranted to recommend probiotics to INRs. [ABSTRACT FROM AUTHOR]

There is a wide spectrum of noninfectious gastrointestinal pathology, causing considerable morbidity and mortality in CVID, where both etiology and effective therapy are under debate. This review will focus on the noninfectious inflammation in the GI tract in CVID patients, covering the both the upper and lower GI tract inflammation, including the liver. The controversy of the CVID enteropathy definition and that of gluten-free diet for celiac-like disease in CVID will be discussed. Furthermore, the review will cover the link between GI inflammation and GI cancer. Finally, the role of gut microbiota, IgA, and genetics and its relationship with CVID enteropathy is scrutinized. The authors reviewed literature from PubMed. The heterogeneity and the unknown mechanism behind CVID enteropathy, and thereby the lack of effective treatment, is one of the key challenges in the field of CVID. Celiac-like disease in CVID is due to immune dysregulation, and a gluten-free diet is therefore not indicated. Gut microbial dysbiosis and mucosal IgA can initiate systemic and local inflammation and is involved in the immune dysregulation in CVID. Considering the heterogeneity of CVID enteropathy, personalized medicine is probably the future for these patients. [ABSTRACT FROM AUTHOR]

Introduction: We previously showed that the rectal mucosal immune environment among men who have sex with men (MSM) engaging in condomless receptive anal intercourse (CRAI) is immunologically distinct from that of men who do not engage in anal intercourse (AI). Here, we further examined these differences with quantitative immunohistochemistry to better understand the geographic distribution of immune markers of interest. Methods: We enrolled a cohort of MSM engaging in CRAI (n = 41) and men who do not engage in AI (n = 21) between October 2013 and April 2015. Participants were healthy, HIV‐negative men aged 18–45 from the metro Atlanta area. We performed rectal mucosal sampling via rigid sigmoidoscopy during two study visits separated by a median of nine weeks and timed with sexual activity for MSM engaging in CRAI. We used standardized, automated immunohistochemistry and quantitative image analysis to investigate the rectal mucosal distribution of neutrophils (MPO), IL‐17‐producing cells (IL‐17) and Tregs (FOXP3) in the lamina propria, and cellular proliferation (Ki67) and adherens junction protein (E‐cadherin) in the epithelium. We examined associations between biomarker expression and the rectal mucosal microbiota composition by 16s rRNA sequencing. Results: Relative to the colonic crypt base, IL‐17, FOXP3, and MPO expression increased towards the rectal lumen, while Ki67 decreased and E‐cadherin was more uniformly distributed. Throughout the rectal mucosa distribution examined, MSM engaging in CRAI had higher mean lamina propria MPO expression (p = 0.04) and epithelial Ki67 (p = 0.04) compared to controls. There were no significant differences in IL‐17, FOXP3 or E‐cadherin expression. We found no significant associations of the five biomarkers with the global rectal microbiota composition or the individual taxa examined. Conclusions: Understanding the mucosal distribution of inflammatory mediators can enhance our knowledge of the earliest events in HIV transmission. Neutrophil enrichment and crypt epithelial cell proliferation likely represent sub‐clinical inflammation in response to CRAI in the rectal mucosa of MSM, which could increase the risk for HIV acquisition. However, the contributory role of the microbiota in mucosal inflammation among MSM remains unclear. HIV prevention may be enhanced by interventions that reduce inflammation or capitalize on the presence of specific inflammatory mechanisms during HIV exposure. [ABSTRACT FROM AUTHOR]

Neutrophils are the most abundant leucocytes in human blood, promptly recruited to the site of tissue injury, where they orchestrate inflammation and tissue repair. The multifaceted functions of neutrophils have been more appreciated during the recent decade, and these cells are now recognized as sophisticated and essential players in infection, cancer and chronic inflammatory diseases. Consequently, our understanding of the role of neutrophils in inflammatory bowel disease (IBD), their immune responses and their ability to shape adaptive immunity in the gut have been recognized. Here, current knowledge on neutrophil responses in IBD and their capacity to influence T cells are summarized with an emphasis on the role of these cells in human disease. [ABSTRACT FROM AUTHOR]

Background: Enteric glial cells (EGC) and mast cells (MC) are intimately associated with gastrointestinal physiological functions. We aimed to investigate EGC‐MC interaction in irritable bowel syndrome (IBS), a gut‐brain disorder linked to increased intestinal permeability, and MC. Methods: Parallel approaches were used to quantify EGC markers in colonic biopsies from healthy controls (HC) and patients with IBS. Data were correlated with MC, vasoactive intestinal polypeptide (VIP) and VIP receptors (VPAC1/VPAC2) expressions, and bacterial translocation through biopsies mounted in Ussing chambers. In addition, we investigated the effects of EGC mediators on colonic permeability and the pharmacological‐induced responses of EGC and MC cell lines. Key Results: Immunofluorescence of IBS colonic mucosa, as well as Western blotting and ELISA of IBS biopsy lysates, revealed increased glial fibrillary intermediate filament (GFAP) expression, indicating EGC activation. Mucosal GFAP correlated with increased MC and VPAC1+MC numbers and decreased VIP+MC, which seemed to control bacterial translocation in HC. In the contrary, EGC activation in IBS correlated with less MC and VPAC1+ MC numbers, and more VIP+ MC. In vitro, MC and EGC cell lines showed intracellular calcium responses to each other's mediators. Furthermore, EGC mediators prevented VIP‐induced MC degranulation, while MC mediators induced a reactive EGC phenotype. In Ussing chambers, EGC mediators decreased paracellular passage through healthy colonic biopsies. Conclusions & Inferences: Findings suggest the involvement of EGC and MC in the control of barrier function in the human colon and indicate a potential EGC‐MC interaction that seems altered in IBS, with detrimental consequences to colonic permeability. Altogether, results suggest that imbalanced EGC‐MC communication contributes to the pathophysiology of IBS. [ABSTRACT FROM AUTHOR]

Background: Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder that affects ~4% of the global population. ReFerm ® is a postbiotic product derived from oat gruel fermented with Lactobacillus plantarum 299v , and it has been shown to have beneficial effects on intestinal permeability in patients with IBS. In this study, we investigated the effects of ReFerm ® on regulators of intestinal permeability, namely mast cells and enteric glial cells., Materials and Methods: A total of 30 patients with moderate to severe IBS were treated with an enema containing ReFerm ® or a placebo twice daily. The patients underwent sigmoidoscopy with biopsies obtained from the distal colon at baseline and after 14 days of treatment. These biopsies were processed in two ways: some were fixed, embedded in paraffin, sectioned, and stained for mast cells and enteric glial cells; others were cryopreserved, lysed, and subjected to Western blotting to analyze the same markers., Results: Treatment with ReFerm ® , but not the placebo, significantly reduced mast cell tryptase protein levels in the biopsy lysates. Although the number of mast cells remained unchanged in colonic biopsies, ReFerm ® treatment significantly reduced mast cell degranulation, a result not observed in the placebo group. Neither ReFerm ® or placebo treatment had an impact on total protein levels or the number of enteric glial cells in the biopsies., Conclusion: ReFerm ® treatment significantly reduced both total mast cell tryptase levels and the degranulation of mast cells in colonic biopsies from patients with IBS, suggesting a decrease in mast cell activity as a potential mechanism underlying the beneficial effects of ReFerm ® . However, further research is required to assess the molecular mechanisms through which ReFerm ® operates in the colons of patients with IBS., Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT05475314., Competing Interests: HI was employed by Nordic Rebalance, which partially financed the study; however, the content of the study was neither influenced nor constrained by this funding. OBi was employed at Linköping University, except for the last 2 months, when she was contracted by Nordic Rebalance as an independent scientific consultant. However, this did not affect or limit the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Biskou, Walter, Israelsen, Winberg, Bednarska and Keita.)

Lifestyle factors like poor maternal diet or antibiotic exposure disrupt early life microbiome assembly in infants, increasing the risk of severe lower respiratory infections (sLRI). Our prior studies in mice indicated that a maternal low-fibre diet (LFD) exacerbates LRI severity in infants by impairing recruitment of plasmacytoid dendritic cells (pDC) and consequently attenuating expansion of lung regulatory T (Treg) cells during pneumonia virus of mice (PVM) infection. Here, we investigated whether maternal dietary fibre intake influences Treg cell phenotypes in the mediastinal lymph nodes (mLN) and lungs of PVM-infected neonatal mice. Using high dimensional flow cytometry, we identified distinct clusters of regulatory T cells (Treg cells), which differed between lungs and mLN during infection, with notably greater effector Treg cell accumulation in the lungs. Compared to high-fibre diet (HFD)-reared pups, frequencies of various effector Treg cell subsets were decreased in the lungs of LFD-reared pups. Particularly, recruitment of chemokine receptor 3 (CXCR3 + ) expressing Treg cells was attenuated in LFD-reared pups, correlating with lower lung expression of CXCL9 and CXCL10 chemokines. The recruitment of this subset in response to PVM infection was similarly impaired in pDC depleted mice or following anti-CXCR3 treatment, increasing immunopathology in the lungs. In summary, PVM infection leads to the sequential recruitment and expansion of distinct Treg cell subsets to the lungs and mLN. The attenuated recruitment of the CXCR3 + subset in LFD-reared pups increases LRI severity, suggesting that strategies to enhance pDCs or CXCL9/CXCL10 expression will lower immune-mediated pathogenesis., (© 2024 The Authors. Immunology published by John Wiley & Sons Ltd.)

Despite the safety profile of subunit vaccines, the inferior immunogenicity hinders their application in the nasal cavity. This study introduces a novel antigen delivery and adjuvant system utilizing mucoadhesive chitosan-catechol (Chic) on silica spiky nanoparticles (Ssp) to enhance immunity through multiple mechanisms. The Chic functionalizes the Ssp surface and incorporates with SARS-CoV-2 spike protein receptor-binding domain (RBD) and toll-like receptor (TLR)9 agonist unmethylated cytosine-guanine (CpG) motif, forming uniform virus-like nanoparticles (Ssp-Chic-RBD-CpG) via electrostatic and covalent interactions. Ssp-Chic-RBD-CpG, mimicking the morphology and function of inactive virions, effectively prolongs the retention time of RBD in the nasal mucosa by 3.92-fold compared to RBD alone, enhances the maturation of dendritic cells (DCs), and facilitates the antigen trafficking to the draining lymph nodes, which subsequently induces a stronger mucosal immunity. Mechanistically, the enhanced chemokine chemokine (C-C motif) ligand 20 (CCL20)-driven DCs recruitment and maturation by Ssp-Chic-RBD-CpG are evidenced by a cell co-culture model. In addition, the overexpression of TLR4/9 and activation of MYD88/NF-κB signaling pathway in activation of DCs are observed. Proof of principle is obtained for RBD, but similar delivery mechanisms can be applied in other protein-based subunit vaccines as well when intranasal administration is needed., (© 2024 Wiley‐VCH GmbH.)

Background: Helicobacter pylori (H. pylori) can evade the host's immune response and persist for a long time on the gastric mucosa. T helper (Th) cells appear to be involved in the control of H. pylori bacteria but promote mucosal inflammation. In contrast, regulatory T cells (Tregs) may reduce inflammation but promote H. pylori persistence. CC motif chemokine receptor 6 (CCR6) is involved in the migration of various cells into inflamed gastric mucosa. In this study, we examined CCR6 + Th cells and CCR6 + Tregs during H. pylori infection in humans., Materials and Methods: Isolation of cells from blood and mucosal biopsies, magnetic separation of В cells, CD4 + and CD4 + CCR6 + CD45RO + T cells, antigen-specific activation, B cell response in vitro, flow cytometry, determination of CD4 + CD25 hi FoxP3 + Tregs and various groups of Th cells., Results: CD4 + CCR6 + blood lymphocytes from healthy donors included Th cells and Tregs. These CCR6 + Th cells produced proinflammatory cytokines and also stimulated plasma cell maturation and antibody production in vitro. H. pylori gastritis and peptic ulcer disease were associated with an increase in the number of circulate CD4 + CCR6 + CD45RO + cells and the percentage of Th1, Th17 and Th1/17 cells in this lymphocyte subgroup. In H. pylori-positive patients, circulating CD4 + CCR6 + cells contained a higher proportion of H. pylori-specific cells compared with their CD4 + CCR6 - counterparts. H. pylori infection strongly increased the content of CD4 + lymphocytes in the inflamed gastric mucosa, with the majority of these CD4 + lymphocytes expressing CCR6. CD4 + CCR6 + lymphocytes from H. pylori-infected stomach included Tregs and in vivo activated T cells, some of which produced interferon-γ without ex vivo stimulation., Conclusion: H. pylori infection causes an increase in the number of mature CD4 + CCR6 + lymphocytes in the blood, with a pro-inflammatory shift in their composition and enrichment of the gastric mucosa with CD4 + CCR6 + lymphocytes, including CCR6 + Th1 cells and Tregs., (© 2024 John Wiley & Sons Ltd.)

Over the course of evolution, mammals and gut commensal microbes have adapted to coexist with each other. This homeostatic coexistence is dependent on an intricate balance between tolerogenic and inflammatory responses directed towards beneficial, commensal microbes and pathogenic intruders, respectively. Immune tolerance towards the gut microflora is largely sustained by immunomodulatory molecules produced by the commensals, which protect the bacteria from immune advances and maintain the gut's unique tolerogenic microenvironment, as well as systemic homeostasis. The identification and characterization of commensal-derived, tolerogenic molecules could lead to their utilization in biomaterials-inspired delivery schemes involving nano/microparticles or hydrogels, and potentially lead to the next generation of commensal-derived therapeutics. Moreover, gut-on-chip technologies could augment the discovery and characterization of influential commensals by providing realistic in vitro models conducive to finicky microbes. In this review, we provide an overview of the gut immune system, describe its intricate relationships with the microflora and identify major genera involved in maintaining tolerogenic responses and peripheral homeostasis. More relevant to biomaterials, we discuss commensal-derived molecules that are known to interface with immune cells and discuss potential strategies for their incorporation into biomaterial-based strategies aimed at culling inflammatory diseases. We hope this review will bridge the current findings in gut immunology, microbiology and biomaterials and spark further investigation into this emerging field. Despite its tremendous potential to culminate into revolutionary therapeutics, the synergy between immunology, microbiology, and biomaterials has only been explored at a superficial level. Strategic incorporation of biomaterial-based technologies may be necessary to fully characterize and capitalize on the rapidly growing repertoire of immunomodulatory molecules derived from commensal microbes. Bioengineers may be able to combine state-of-the-art delivery platforms with immunomodulatory cues from commensals to provide a more holistic approach to combating inflammatory disease. This interdisciplinary approach could potentiate a neoteric field of research - "commensal-inspired" therapeutics with the promise of revolutionizing the treatment of inflammatory disease. [Display omitted] [ABSTRACT FROM AUTHOR]

The microbiome of the female genital tract (FGT) is closely linked to reproductive health outcomes. Diverse, anaerobe-dominated communities with low Lactobacillus abundance are associated with a number of adverse reproductive outcomes, such as preterm birth, cervical dysplasia, and sexually transmitted infections (STIs), including HIV. Vaginal dysbiosis is associated with local mucosal inflammation, which likely serves as a biological mediator of poor reproductive outcomes. Yet the precise mechanisms of this FGT inflammation remain unclear. Studies in humans have been complicated by confounding demographic, behavioral, and clinical variables. Specifically, hormonal contraception is associated both with changes in the vaginal microbiome and with mucosal inflammation. In this study, we examined the transcriptional landscape of cervical cell populations in a cohort of South African women with differing vaginal microbial community types. We also investigate effects of reproductive hormones on the transcriptional profiles of cervical cells, focusing on the contraceptive depot medroxyprogesterone acetate (DMPA), the most common form of contraception in sub-Saharan Africa. We found that antigen presenting cells (APCs) are key mediators of microbiome associated FGT inflammation. We also found that DMPA is associated with significant transcriptional changes across multiple cell lineages, with some shared and some distinct pathways compared to the inflammatory signature seen with dysbiosis. These results highlight the importance of an integrated, systems-level approach to understanding host-microbe interactions, with an appreciation for important variables, such as reproductive hormones, in the complex system of the FGT mucosa. [ABSTRACT FROM AUTHOR]

Lung-localized CD4 T cells play a critical role in the control of influenza virus infection and can provide broadly protective immunity. However, current influenza vaccination strategies primarily target influenza hemagglutinin (HA) and are administered peripherally to induce neutralizing antibodies. We have used an intranasal vaccination strategy targeting the highly conserved influenza nucleoprotein (NP) to elicit broadly protective lung-localized CD4 T cell responses. The vaccine platform consists of a self-assembling nanolipoprotein particle (NLP) linked to NP with an adjuvant. We have evaluated the functionality, in vivo localization, and persistence of the T cells elicited. Our study revealed that intranasal vaccination elicits a polyfunctional subset of lung-localized CD4 T cells that persist long term. A subset of these lung CD4 T cells localize to the airway, where they can act as early responders following encounter with cognate antigen. Polyfunctional CD4 T cells isolated from airway and lung tissue produce significantly more effector cytokines IFN-y and TNF-α, as well as cytotoxic functionality. When adoptively transferred to naive recipients, CD4 T cells from NLP:NP-immunized lung were sufficient to mediate 100% survival from lethal challenge with H1N1 influenza virus. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency (CVID) is the most common symptomatic primary antibody immunodeficiency, characterized by reduced serum levels of IgG, IgA, and/or IgM. The vast majority of CVID patients have polygenic inheritance. Immune dysfunction in CVID can frequently involve the gastrointestinal tract and lung. Few studies have started to investigate the gut microbiota profile in CVID patients. Overall, the results suggest that in CVID patients there is a reduction of alpha and beta diversity compared to controls. In addition, these patients can exhibit increased plasma levels of lipopolysaccharide (LPS) and markers (sCD14 and sCD25) of systemic immune cell activation. CVID patients with enteropathy exhibit decreased IgA expression in duodenal tissue. Mouse models for CVID unsatisfactorily recapitulate the polygenic causes of human CVID. The molecular pathways by which gut microbiota contribute to systemic inflammation and possibly tumorigenesis in CVID patients remain poorly understood. Several fundamental questions concerning the relationships between gut microbiota and the development of chronic inflammatory conditions, autoimmune disorders or cancer in CVID patients remain unanswered. Moreover, it is unknown whether it is possible to modify the microbiome and the outcome of CVID patients through specific therapeutic interventions. [ABSTRACT FROM AUTHOR]

Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier γδ T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 μg/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. γδ T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated γδ T cell null (Tcrd(-/-) ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd(-/-) ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd(-/-) ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of γδ T cells from human peripheral blood (h-γδ T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-γδ T cells exhibited rapid expansion and robust IFN-γ secretion. When h-γδ T cells were injected into ZOL-treated immunodeficient (Rag2(-/-) ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2(-/-) ZOL mice did not develop osteonecrosis. The results indicate that γδ T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ.

The microbiome of the female genital tract (FGT) is closely linked to reproductive health outcomes. Diverse, anaerobe-dominated communities with low Lactobacillus abundance are associated with a number of adverse reproductive outcomes, such as preterm birth, cervical dysplasia, and sexually transmitted infections (STIs), including HIV. Vaginal dysbiosis is associated with local mucosal inflammation, which likely serves as a biological mediator of poor reproductive outcomes. Yet the precise mechanisms of this FGT inflammation remain unclear. Studies in humans have been complicated by confounding demographic, behavioral, and clinical variables. Specifically, hormonal contraception is associated both with changes in the vaginal microbiome and with mucosal inflammation. In this study, we examined the transcriptional landscape of cervical cell populations in a cohort of South African women with differing vaginal microbial community types. We also investigate effects of reproductive hormones on the transcriptional profiles of cervical cells, focusing on the contraceptive depot medroxyprogesterone acetate (DMPA), the most common form of contraception in sub-Saharan Africa. We found that antigen presenting cells (APCs) are key mediators of microbiome associated FGT inflammation. We also found that DMPA is associated with significant transcriptional changes across multiple cell lineages, with some shared and some distinct pathways compared to the inflammatory signature seen with dysbiosis. These results highlight the importance of an integrated, systems-level approach to understanding host-microbe interactions, with an appreciation for important variables, such as reproductive hormones, in the complex system of the FGT mucosa.

Common variable immunodeficiency (CVID) is the most common symptomatic primary antibody immunodeficiency, characterized by reduced serum levels of IgG, IgA, and/or IgM. The vast majority of CVID patients have polygenic inheritance. Immune dysfunction in CVID can frequently involve the gastrointestinal tract and lung. Few studies have started to investigate the gut microbiota profile in CVID patients. Overall, the results suggest that in CVID patients there is a reduction of alpha and beta diversity compared to controls. In addition, these patients can exhibit increased plasma levels of lipopolysaccharide (LPS) and markers (sCD14 and sCD25) of systemic immune cell activation. CVID patients with enteropathy exhibit decreased IgA expression in duodenal tissue. Mouse models for CVID unsatisfactorily recapitulate the polygenic causes of human CVID. The molecular pathways by which gut microbiota contribute to systemic inflammation and possibly tumorigenesis in CVID patients remain poorly understood. Several fundamental questions concerning the relationships between gut microbiota and the development of chronic inflammatory conditions, autoimmune disorders or cancer in CVID patients remain unanswered. Moreover, it is unknown whether it is possible to modify the microbiome and the outcome of CVID patients through specific therapeutic interventions.

Summary: Differentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here, we show that intestine-draining mesenteric lymph nodes (MLNs), not intestine proper, are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their upregulation of integrin β7. Stat3-dependent induction of RORγt, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFB-directed Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLNs and accumulation of the cells in the lamina propria.

The mucosal immune system - consisting of adaptive and innate immune cells as well as the epithelium - is profoundly influenced by its microbial environment. There is now growing evidence that the converse is also true, that the immune system shapes the composition of the intestinal microbiome. During conditions of health, this bidirectional interaction achieves a homeostasis in which inappropriate immune responses to non-pathogenic microbes are averted and immune activity suppresses blooms of potentially pathogenic microbes (pathobionts). Genetic alteration in immune/epithelial function can affect host gardening of the intestinal microbiome, contributing to the diversity of intestinal microbiota within a population and in some cases allowing for unfavorable microbial ecologies (dysbiosis) that confer disease susceptibility.

Local respiratory allergy (LRA) is defined by the negativity of atopy tests, a clinical history suggestive of airway allergy and a positive response to the nasal and/or bronchial allergen challenge. The clinical spectrum of LRA is comprised of three conditions: local allergic rhinitis (LAR) and local allergic asthma in non-atopic patients, and dual allergic rhinitis (coexistence of allergic rhinitis and LAR) in atopic individuals. LRA is an independent disease phenotype not progressing to atopy over time, but naturally evolving to the clinical worsening and the onset of comorbidities. Published data suggests that LRA is mediated through the mucosal synthesis of allergen-specific (s)IgE, which binds to FcϵRI on resident mast cells, and in >50% of cases traffics to the blood stream to sensitize circulating basophils. To date, 4 clinical trials have demonstrated the capacity of allergen immunotherapy (AIT) to decrease nasal, conjunctival and bronchial symptoms, to improve quality of life, to increase the threshold dose of allergen eliciting respiratory symptoms, and to induce serum sIgG4 in LRA individuals. Collectively, these data indicate that local allergy is a relevant disease mechanisms in both atopic and non-atopic patients with airway diseases.

The mechanism of generation of regulatory T cells (Treg) remains incompletely understood. Recent studies show that CD83 has immune regulatory functions. This study aims to investigate the role of epithelial cell‐derived CD83 in the restoration of immune tolerance in the airway mucosa by inducing the Treg differentiation. In this study, CD83 and ovalbumin (OVA)‐carrying exosomes were generated from airway epithelial cells. An airway allergy mouse model was developed to test the role of CD83/OVA‐carrying exosomes in the suppression of airway allergy by inducing Treg generation. We observed that mouse airway epithelial cells expressed CD83 that could be up‐regulated by CD40 ligand. The CD83 deficiency in epithelial cells retarded the Treg generation in the airway mucosa. CD83 up‐regulated transforming growth factor‐β‐inducible early gene 1 expression in CD4+ T cells to promote Foxp3 expression. Exposure of primed CD4+ T cells to CD83/OVA‐carrying exosomes promoted antigen‐specific Treg generation. Administration of CD83/OVA‐carrying exosomes inhibited experimental airway allergic response. In summary, airway epithelial cells express CD83 that is required in the Treg differentiation in the airway mucosa. Administration of CD83/OVA‐carrying exosomes can inhibit airway allergy that has the translation potential in the treatment of airway allergic disorders. [ABSTRACT FROM AUTHOR]

Neuroimmune interactions have been revealed to be at the centre stage of tissue defence, organ homeostasis, and organismal physiology. Neuronal and immune cell subsets have been shown to colocalize in discrete tissue environments, forming neuroimmune cell units that constitute the basis for bidirectional interactions. These multitissue units drive coordinated neuroimmune responses to local and systemic signals, which represents an important challenge to our current views of mucosal physiology and immune regulation. In this review, we focus on the impact of reciprocal neuroimmune interactions, focusing on the anatomy of neuronal innervation and on the neuronal regulation of immune cells in peripheral tissues. Finally, we shed light on recent studies that explore how neuroimmune interactions maximise sensing and integration of environmental aggressions, modulating immune function in health and disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • SLPI prevents tissue destruction and regulates inflammation at barrier tissues. • SLPI production and function is deregulated in several inflammatory diseases. • Excessive expression of SLPI in cancer cells may promote their metastatic potential. The immune system is continuously challenged with large quantities of exogenous antigens at the barriers between the external environment and internal human tissues. Antimicrobial activity is essential at these sites, though the immune responses must be tightly regulated to prevent tissue destruction by inflammation. Secretory Leukocyte Protease Inhibitor (SLPI) is an evolutionarily conserved, pleiotropic protein expressed at mucosal surfaces, mainly by epithelial cells. SLPI inhibits proteases, exerts antimicrobial activity and inhibits nuclear factor-kappa B (NF-κB)-mediated inflammatory gene transcription. SLPI maintains homeostasis at barrier tissues by preventing tissue destruction and regulating the threshold of inflammatory immune responses, while protecting the host from infection. However, excessive expression of SLPI in cancer cells may have detrimental consequences, as recent studies demonstrate that overexpression of SLPI increases the metastatic potential of epithelial tumors. Here, we review the varied functions of SLPI in the respiratory tract, skin, gastrointestinal tract and genitourinary tract, and then discuss the mechanisms by which SLPI may contribute to cancer. [ABSTRACT FROM AUTHOR]

Local respiratory allergy (LRA) is defined by the negativity of atopy tests, a clinical history suggestive of airway allergy and a positive response to the nasal and/or bronchial allergen challenge. The clinical spectrum of LRA is comprised of three conditions: local allergic rhinitis (LAR) and local allergic asthma in non-atopic patients, and dual allergic rhinitis (coexistence of allergic rhinitis and LAR) in atopic individuals. LRA is an independent disease phenotype not progressing to atopy over time, but naturally evolving to the clinical worsening and the onset of comorbidities. Published data suggests that LRA is mediated through the mucosal synthesis of allergen-specific (s)IgE, which binds to FcϵRI on resident mast cells, and in >50% of cases traffics to the blood stream to sensitize circulating basophils. To date, 4 clinical trials have demonstrated the capacity of allergen immunotherapy (AIT) to decrease nasal, conjunctival and bronchial symptoms, to improve quality of life, to increase the threshold dose of allergen eliciting respiratory symptoms, and to induce serum sIgG4 in LRA individuals. Collectively, these data indicate that local allergy is a relevant disease mechanisms in both atopic and non-atopic patients with airway diseases. [ABSTRACT FROM AUTHOR]

Autoantibodies against the enzyme transglutaminase 2 (TG2) are characteristic of celiac disease (CeD), and TG2-specific immunoglobulin (Ig) A plasma cells are abundant in gut biopsies of patients. Here, we describe the corresponding population of autoreactive B cells in blood. Circulating TG2-specific IgA cells are present in untreated patients on a gluten-containing diet but not in controls. They are clonally related to TG2-specific small intestinal plasma cells, and they express gut-homing molecules, indicating that they are plasma cell precursors. Unlike other IgA-switched cells, the TG2-specific cells are negative for CD27, placing them in the double-negative (IgD−CD27−) category. They have a plasmablast or activated memory B cell phenotype, and they harbor fewer variable region mutations than other IgA cells. Based on their similarity to naive B cells, we propose that autoreactive IgA cells in CeD are generated mainly through chronic recruitment of naive B cells via an extrafollicular response involving gluten-specific CD4+ T cells. [Display omitted] • TG2-specific IgA+ B cells are present in the blood of untreated celiac disease patients • The autoreactive B cells are gut homing and clonally related to duodenal plasma cells • Most of the circulating cells are activated pre-plasma cells that are CD27 negative • The phenotype of TG2-specific B cells is mirrored by in vitro stimulation of naive B cells Celiac disease is associated with IgA-class autoantibodies to transglutaminase 2 (TG2). Lindeman et al. identify TG2-specific IgA+ B cells in the blood of celiac disease patients. These cells are gut-homing pre-plasma cells with a phenotype suggesting that they arise from continuous recruitment of naive B cells during a chronic immune response. [ABSTRACT FROM AUTHOR]

Respiratory tract infections are among the most common infections in dromedary camels, with a high impact on animal health, production, and welfare. Tissue-specific distribution of immune cells is one of the important factors that influence the nature and outcome of the immune response to pathogens. Several protocols have recently been described for the flow cytometric analysis of immune cells in the lung tissue of several species. However, no such protocol currently exists for dromedary camels. The aim of the present study was, therefore, to establish a flow cytometric protocol for the identification of immune cell populations in the camel lung tissue and the evaluation of some of their phenotypic and functional properties. Combined staining of camel lung leukocytes with monoclonal antibodies to the pan-leukocyte marker CD45 and the myeloid cell marker CD172a allowed the identification of myeloid cells (CD45+CD172a+) and lymphoid cells (CD45+CD172a−) in the lung of healthy camels. The cell adhesion molecules CD11a and CD18 were found in a higher abundance on myeloid cells compared to lymphoid cells. Based on their differential expression of the LPS receptor CD14, macrophages (CD172a+CD14high cells) were identified as the most abundant immune cell population in the camel lung tissue. In contrast to their dominance in camel peripheral blood, granulocytes (CD172a+CD14low) presented only a minor population in the lung tissue. The higher frequency of γδ T cells in the lung tissue than in peripheral blood suggests a role for these cells in the pulmonary immune system. Flow cytometric analysis of bacterial phagocytosis and ROS production upon bacterial stimulation revealed high antimicrobial activity of camel lung phagocytes, which was comparable with the antimicrobial activity of blood granulocytes. Comparative analysis of immune cell distribution between the cranial and caudal lobes of the camel lung revealed a higher frequency of granulocytes and a lower frequency of macrophages in the cranial compared to the caudal lung lobe. In addition, the higher frequency of cells expressing the M2 macrophage marker CD163 in the caudal lung tissue, with a slightly higher fraction of MHCII-positive cells (M1 phenotype) in the cranial lung tissue, may suggest the distribution of different macrophage subtypes in the different lobes of the camel lung. Such differences between lung lobes could influence the effectiveness of the immune response to infection or vaccination with respiratory pathogens. Collectively, the present study identified some similarities and differences between camels and other farm animals regarding the distribution of the main immune cell populations in their lungs. Further studies are required for comprehensive immunophenotyping of the cellular pulmonary immune system in camels.

Among antibodies, IgA is unique because it has evolved to be secreted onto mucosal surfaces. The structure of IgA and the associated secretory component allow IgA to survive the highly proteolytic environment of mucosal surfaces but also substantially limit IgA's ability to activate effector functions on immune cells. Despite these characteristics, IgA is critical for both preventing enteric infections and shaping the local microbiome. IgA's function is determined by a distinct antigen-binding repertoire, composed of antibodies with a variety of specificities, from permissive polyspecificity to cross-reactivity to exquisite specificity to a single epitope, which act together to regulate intestinal bacteria. Development of the unique function and specificities of IgA is shaped by local cues provided by the gut-associated lymphoid tissue, driven by the constantly changing environment of the intestine and microbiota. [ABSTRACT FROM AUTHOR]

The inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, progressive, inflammatory conditions of the gastrointestinal tract. Imbalance in the gut microbial community, or dysbiosis, and the subsequent immune response, represent the critical relationship between genetic susceptibility, microbes, and environment factors, that result in IBD. Gastrointestinal pathogens – a common cause of dysbiosis – have been implicated as an environmental trigger in new onset IBD, as well as flare of existing IBD. In this article, we systematically review clinical data regarding the association between specific gastrointestinal pathogens and IBD. Numerous bacteria, viruses, fungi, and parasites have been implicated in the pathogenesis of IBD, and exacerbations of existing disease. In this article, we will also specifically discuss the less recognized microbes that have an inverse association with IBD, including certain bacterial pathogens, such as Helicobacter pylori, and parasites, such as Trichuris species. Future prospective and experimental studies are required to establish causality and clarify potential mechanisms of enteric pathogens in modifying the risk and course of IBD. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases are common, complex, immune-mediated conditions with a sharply rising global prevalence. While major advances since 2000 have provided strong mechanistic clues implicating a de-regulation in the normal interaction among host genetics, immunity, microbiome, and the environment, more recent progress has generated entirely new hypotheses and also further refined older disease concepts. In this review, we focus specifically on these novel developments in the pathogenesis of ulcerative colitis.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells present at considerable frequencies in human blood and barrier tissues, armed with an expanding array of effector functions in response to homeostatic perturbations. Analogous to other barrier immune cells, their phenotype and function is driven by crosstalk with host and dynamic environmental factors, most pertinently the microbiome. Given their distribution, they must function in diverse extracellular milieus. Tissue-specific and adapted functions of barrier immune cells are shaped by transcriptional programs and regulated through a blend of local cellular, inflammatory, physiological, and metabolic mediators unique to each microenvironment. This review compares the phenotype and function of MAIT cells with other barrier immune cells, highlighting potential areas for future exploration. Appreciation of MAIT cell biology within tissues is crucial to understanding their niche in health and disease.

Worldwide, lung cancer, particularly K-ras mutant lung adenocarcinoma (KM-LUAD), is the leading cause of cancer mortality because of its high incidence and low cure rate. To treat and prevent KM-LUAD, there is an urgent unmet need for alternative strategies targeting downstream effectors of K-ras and/or its cooperating pathways. Tumor-promoting inflammation, an enabling hallmark of cancer, strongly participates in the development and progression of KM-LUAD. However, our knowledge of the dynamic inflammatory mechanisms, immunomodulatory pathways, and cell-specific molecular signals mediating K-ras-induced lung tumorigenesis is substantially deficient. Nevertheless, within this signaling complexity, an inflammatory pathway is emerging as a druggable target: signal transducer and activator of transcription 3 (STAT3). Here, we review the cell type-specific functions of STAT3 in the pathogenesis and progression of KM-LUAD that could serve as a new target for personalized preventive and therapeutic intervention for this intractable form of lung cancer.

Toxoplasma gondii infection occurs through the oral route, but we lack important information about how the parasite interacts with the host immune system in the intestine. We used two-photon laser-scanning microscopy in conjunction with a mouse model of oral T. gondii infection to address this issue. T. gondii established discrete foci of infection in the small intestine, eliciting the recruitment and transepithelial migration of neutrophils and inflammatory monocytes. Neutrophils accounted for a high proportion of actively invaded cells, and we provide evidence for a role for transmigrating neutrophils and other immune cells in the spread of T. gondii infection through the lumen of the intestine. Our data identify neutrophils as motile reservoirs of T. gondii infection and suggest a surprising retrograde pathway for parasite spread in the intestine.

Periodontitis, one of the most common infectious diseases in humans, is characterized by inflammation of the periodontal tissue and subsequent destruction of the alveolar bone, which ultimately leads to tooth loss. Recently, it was revealed that the osteoclastic bone damage that occurs during periodontitis is dependent on the receptor activator of NF-kB ligand (RANKL) produced by osteoblastic cells and periodontal ligament cells. Immune cells provide essential cues for the RANKL induction that takes place during periodontal inflammation. The knowledge accumulated and experimental tools established in the field of "osteoimmunology" have made crucial contributions to a better understanding of periodontitis pathogenesis and, reciprocally, the investigation of periodontitis has provided important insights into the field. This review discusses the molecular mechanisms underlying periodontal bone loss by focusing on the osteoimmune interactions and RANKL. [ABSTRACT FROM AUTHOR]

In recent years, it has become apparent that imbalances in the gastrointestinal system can impact organs beyond the intestine such as the lungs. Given the established ability of probiotics to modulate the immune system by interacting with gastrointestinal cells, our research aimed to investigate whether administering the probiotic strain Bacillus subtilis-597 could mitigate the outcome of influenza virus infection in pigs. Pigs were fed a diet either with or without the probiotic strain B. subtilis-597 for 14 days before being intranasally inoculated with a swine influenza A H1N2 strain (1 C.2 lineage). Throughout the study, we collected fecal samples, blood samples, and nasal swabs to examine viral shedding and immune gene expression. After seven days of infection, the pigs were euthanized, and lung and ileum tissues were collected for gene expression analysis and pathological examination. Our findings indicate that the administration of B. subtilis-597 exhibit potential in reducing lung lesions, possibly attributable to a general suppression of the immune system as indicated by reduced C-reactive protein (CRP) levels in serum, decreased expression of interferon-stimulated genes (ISGs), and localized reduction of the inflammatory marker serum amyloid A (SAA) in ileum tissue. Notably, the immune-modulatory effects of B. subtilis-597 appeared to be unrelated to the gastrointestinal microbiota, as the composition remained unaltered by both the influenza infection and the administration of B. subtilis-597., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KW, LHBH, GV, DS and EJB are employees of Chr Hansen A/S. ARW has received research funding from Chr Hansen A/S. The other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Mucosal T cells play a major role in inflammatory bowel disease (IBD). However, their immunometabolism during intestinal inflammation is poorly understood. Due to its impact on cellular metabolism and proinflammatory immune cell function, we here focus on the enzyme ATP citrate lyase (ACLY) in mucosal T cell immunometabolism and its relevance for IBD., Design: ACLY expression and its immunometabolic impact on colitogenic T cell function were analysed in mucosal T cells from patients with IBD and in two experimental colitis models., Results: ACLY was markedly expressed in colon tissue under steady-state conditions but was significantly downregulated in lamina propria mononuclear cells in experimental dextran sodium sulfate-induced colitis and in CD4 + and to a lesser extent in CD8 + T cells infiltrating the inflamed gut in patients with IBD. ACLY-deficient CD4 + T cells showed an impaired capacity to induce intestinal inflammation in a transfer colitis model as compared with wild-type T cells. Assessment of T cell immunometabolism revealed that ACLY deficiency dampened the production of IBD-relevant cytokines and impaired glycolytic ATP production but enriched metabolites involved in the biosynthesis of phospholipids and phosphatidylcholine. Interestingly, the short-chain fatty acid butyrate was identified as a potent suppressor of ACLY expression in T cells, while IL-36α and resolvin E1 induced ACLY levels. In a translational approach, in vivo administration of the butyrate prodrug tributyrin downregulated mucosal infiltration of ACLY high CD4 + T cells and ameliorated chronic colitis., Conclusion: ACLY controls mucosal T cell immunometabolism and experimental colitis. Therapeutic modulation of ACLY expression in T cells emerges as a novel strategy to promote the resolution of intestinal inflammation., Competing Interests: Competing interests: MFN has served as an advisor for Pentax, Giuliani, MSD, Abbvie, Janssen, Takeda and Boehringer. Moreover, MFN serves as an associated editor of the journal Gut. The remaining authors disclose no conflicts., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Mucosal-associated invariant T (MAIT) cells are innate-like T cells present at considerable frequencies in human blood and barrier tissues, armed with an expanding array of effector functions in response to homeostatic perturbations. Analogous to other barrier immune cells, their phenotype and function is driven by crosstalk with host and dynamic environmental factors, most pertinently the microbiome. Given their distribution, they must function in diverse extracellular milieus. Tissue-specific and adapted functions of barrier immune cells are shaped by transcriptional programs and regulated through a blend of local cellular, inflammatory, physiological, and metabolic mediators unique to each microenvironment. This review compares the phenotype and function of MAIT cells with other barrier immune cells, highlighting potential areas for future exploration. Appreciation of MAIT cell biology within tissues is crucial to understanding their niche in health and disease. [ABSTRACT FROM AUTHOR]

The balance of type 1 and type 2 immune responses plays a crucial role in anti-helminth immunity and can either support chronic infection or drive type 2 mediated expulsion of the parasite. Helminth antigens and secreted molecules directly influence this balance and induce a favorable immunological environment for the parasite’s survival. However, less is known if the site of infection also influences the balance of type 1 and type 2 immunity. Here, we report that tissue-specific immune responses are mounted against helminth antigens, which elicited strong IL-4 responses when injected into the skin, while the same antigen, delivered into the intestinal subserosa, induced increased IFN-γ and reduced Th2 responses. Immune responses in individual mesenteric lymph nodes that drain defined regions of the intestine furthermore displayed a site-specific pattern of type 1 and type 2 immunity after Schistosoma mansoni or Heligmosomoides polygyrus infection. S. mansoni egg-specific Th2 responses were detectable in all mesenteric lymph nodes but Th1 responses were only present in those draining the colon, while H. polygyrus infection elicited mixed Th1 and Th2 responses in the lymph nodes associated with the site of infection. Similar site-specific type 1 and type 2 immune responses were observed in the draining lymph nodes after the controlled delivery of S. mansoni eggs into different segments of the small and large intestine using microsurgical techniques. Different subsets of intestinal dendritic cells were hereby responsible for the uptake and priming of Th1 and Th2 responses against helminth antigens. Migratory CD11b+CD103− and especially CD11b+CD103+ DC2s transported S. mansoni egg antigens to the draining lymph nodes to induce Th1 and Th2 responses, while CD103+ DC1s induced only IFN-γ responses. In contrast, H. polygyrus antigens were predominantly transported by CD11b+CD103− DC2s and CD103+ DC1s and all DC subsets induced similar Th1 but weaker Th2 responses, compared to S. mansoni egg antigens. The development of adaptive anti-helminth immune responses is therefore influenced by the antigen itself, the uptake and priming characteristics of antigen-positive dendritic cell subsets and the site of infection, which shape the level of Th1 and Th2 responses in order to create a favorable immunological environment for the parasite.

ABSTRACT Jose Lemme-Dumit works in the field of mucosal immunology and vaccines. In this mSphere of Influence article, he reflects on how two papers, “Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium” by Sato et al. (T. Sato, D. E. Stange, M. Ferrante, R. G. J. Vries, et al., Gastroenterology 141:1762–1772, 2011, https://doi.org/10.1053/j.gastro.2011.07.050) and “T helper cell cytokines modulate intestinal stem cell renewal and differentiation” by Biton et al. (M. Biton, A. L. Haber, N. Rogel, G. Burgin, et al., Cell 175:1307–1320.E22, 2018, https://doi.org/10.1016/j.cell.2018.10.008), have influenced his research by describing the development of intestinal organoid cultures and implementation of high-throughput sequencing analysis. The combination of these forefront technologies has expanded opportunities for mechanistic interrogation of host immunity to enteric pathogens.

Unique structural features characterize the P2X7 receptor with respect to other P2X family members. Dual gating by eATP and regulated expression of P2X7 can imprint distinct outcomes to the T cell depending on the metabolic fitness and/or developmental stage. In the thymus, signaling by P2X7 contributes to γδ T cell lineage choice. In secondary lymphoid organs, P2X7 stimulation promotes Th1/Th17 polarization of CD4+ naïve cells, Tregs conversion to Th17 cells and cell death of Tfh cells that are not stimulated by cognate antigen. Moreover, P2X7 stimulation in eATP rich microenvironments, such as damaged and/or inflamed tissues as well as tumors, induces cell death of various T cell effector subsets.