Mucosal Immunology最新文献

The major fungal allergen Alt a 1 from Alternaria alternata is linked to allergic asthma. We assessed its biological role in nutritional immunity to iron and its allergenic potential using in silico, in vitro, and in vivo approaches. Alternaria was cultured with or without iron and with quercetin to promote iron-quercetin (FeQ2) complexes, followed by Alt a 1 expression analysis, which revealed enhanced expression under iron deficiency and reduced levels by addition of quercetin. In silico and RBLsx38 mast cell degranulation assays showed that FeQ2 binding to Alt a 1 (holoAlt a 1) masked the IgE epitope Y87-D96 by promoting tetramer-formation of Alt a 1, reducing IgE binding and antigen-specific degranulation compared to ligand-free Alt a 1 (apoAlt a 1). In BALB/c mice, intranasal exposure to apo- or holoAlt a 1 before intraperitoneal Alt a 1/alum sensitization demonstrated that holoAlt a 1 exposure led to lower allergen-specific antibody titers, fewer mature antigen-presenting cells, increased regulatory T cells, and reduced allergic symptoms upon challenge compared to mice exposed to apoAlt a 1. Additionally, human PBMCs incubated with holoAlt a 1 exhibited fewer Th cells and plasmablasts, but more immature B cells with a higher iron content than those exposed to apoAlt a 1. These findings demonstrate that iron-poor conditions trigger nutritional immunity in Alternaria, increasing Alt a 1 expression, and that apoAlt a 1, through iron scavenging, has greater sensitizing capacity than the holo form, influencing immune responses relevant to allergic asthma. One Sentence Summary: Iron-poor conditions activate nutritional immunity in Alternaria, increasing the expression of allergenic dimeric Alt a 1, whereas its iron-bound tetrameric form does not trigger an immune response and thus prevents allergy development.

Identification of pathways preventing timely recovery from acute respiratory viral infection is under-studied but essential for long-term health. Using unbiased proteomics, we reveal an unexpected, reduction in lung basement membrane proteins 21 days after influenza infection when mice had symptomatically recovered. Basement membrane provides a critical scaffold for heterogeneous cell types and the proteins they secrete/express at the endothelial and epithelial barrier. Further peptide location fingerprinting analysis shows inherent structure-associated changes within core collagen IV and laminin components, particularly within the NC1 domains of collagen IV. Our results imply lingering damage to the basement membrane network despite symptomatic recovery from viral infection. Surprisingly, similar structure-associated changes in laminin and collagen IV components are also observed in non-infected, aged mice indicating that inflammation-driven basement membrane degeneration may contribute to tissue ageing. Interestingly, macrophages in regions deficient in basement membrane express collagen IV and laminin chains. Repair of the basement membrane should therefore be targeted to improve overall lung health. Non-technical summary: Lung virus infection is a constant global threat, despite developments in vaccination and anti-viral treatments. We have a deep understanding of this inflammatory condition but less is known about the drivers of persistent problems, including fatigue and breathlessness as illustrated by "long COVID". Here, we reveal a novel finding that a critical structure in the lung (the basement membrane) remains damaged after the influenza virus and symptoms have cleared. This structure supports a variety of cells and forms a barrier that lines the airspaces. It also regulates fluid and cell movement into these airspaces. Remarkably, we show that similar changes after virus infection are also evident in aged lungs, which implies that lung complications with age may be due to repeated inflammation. By identifying these persistent basement membrane changes, we provide an entirely novel area to target with new medicines to treat complications arising from viral infection.

Endometrial injury triggers inflammation responses, and persistent inflammation is a recognized cause of infertility. Emerging evidence underscores the critical role of the vagus nerve in modulating immunity. Although vagotomy is known to induce systemic inflammation, the specific mechanism by which the vagus nerve regulates uterine health is still unclear. In this study, we employed a vagotomy model to investigate the therapeutic potential of pantothenic acid in alleviating endometrial injury. Our results showed that left cervical vagotomy reduces the integrity of the endometrium and the expression of barrier proteins such as Claudin-3, Occludin, and ZO-1. Vagotomy increases the levels of inflammatory cytokines (TNF-α and IL-1β) and LPS in uterine tissue and serum through the NF-κB signaling pathway. Furthermore, we found that vagotomy promotes ferroptosis by decreasing the protein expression of SLC7A11 and GPX4 and increasing the level of COX2. Vagotomy significantly altered thecompositionof the uterine microbiota,characterized by a significant enrichment of Rodentibacter and a depletion of Vagococcus and Acetobacter. Next, we found that vagotomy can cause an increase in serum levels of lysoPE 20:4, antipyrine, and lysoPE18:2, as well as a decrease in levels of hexanoyl-L-Carnitine and pantothenic acid. When pantothenic acid was supplemented, the endometrial injury caused by vagotomy was reversed. Pantothenic acid increased the expression of barrier proteins in the endometrium and reduced the content of inflammatory cytokines in uterine tissue and serum of mice. At the same time, pantothenic acid also reversed the degree of ferroptosis induced by vagotomy in uterine tissue and serum. Our study demonstrates that vagotomy disrupts the endometrial microbiota and promotes endometrium injury and the markers of ferroptosis via the NF-κB pathway. Pantothenic acid supplementation alleviates vagus nerve-mediated endometrial injury. These results highlight that vagus nerve regulation of uterine health through pantothenic acid is a promising strategy.

The placental intervillous space is a unique immunological niche where circulating maternal immune cells come into direct contact with the fetal syncytiotrophoblast. While adaptations in immune cell composition are known to occur in the maternal decidua throughout pregnancy, it remains unclear whether similar changes take place in the intervillous space. Here, we demonstrate that the intervillous immune cell composition undergoes dynamic changes during pregnancy, with a decreased proportion of NK cells and an increased proportion of T cells from second trimester to term pregnancy. Interestingly, second-trimester intervillous NK cells were predominantly CD56^brightCD16^- with high expression of CD49a, CD103, and CD69. This phenotype more closely resembled tissue-resident decidual NK (dNK) cells than peripheral NK cells. Conditioned medium from fetal villous tissue did not induce changes in peripheral NK cell phenotype, suggesting that the observed phenotypic alterations are not driven by soluble factors from the villous microenvironment. Analysis of predicted ligand-receptor complexes suggested that NK cells may provide important growth signals to the syncytiotrophoblast. In conclusion, immunological adaptations occur in the intervillous space throughout pregnancy and the presence of dNK-like cells in the intervillous space underscores a potential role for these cells in maintaining a balanced immune environment at the maternal-fetal interface.

Immunological memory elicited either through previous or ongoing M. tuberculosis (Mtb) infection provides a critical mechanism by which hosts protect against re-infection and disease progression upon Mtb re-exposure. Conversely, the uneven competition between distinct Mtb strains suggest certain bacterial clades have enhanced ability to spread across communities and circulate globally, potentially by evading memory responses gained by prior infection with genomically different strains. To address whether memory responses induced by one strain can protect against a genetically distinct strain, we conducted a heterologous reinfection study in cynomolgus macaques involving primary infection by a Lineage 4 Erdman Mtb strain and subsequent re-challenge by a Lineage 2 strain, HT-L2. Recent epidemiologic studies have shown that the clade to which HT-L2 belongs has been spreading successfully over the last decade in Lima, Peru. Here, through microbiologic, PET-CT imaging and sequencing of Mtb genomic barcodes, we show that reinfected animals developed fewer lung lesions and controlled both pulmonary and disseminated forms of infection better than naïve animals without prior exposure to Mtb. Our data support that protection against reinfection is not limited by Mtb lineage, providing optimism that vaccines can be effective across populations and geographic locations.

Intravenous (IV) vaccination with Bacillus Calmette-Guerin (BCG) mediates sterilizing immunity against Mycobacterium tuberculosis (Mtb) in rhesus macaques but the cellular mechanisms underlying protection are undefined. We used mass cytometry (CyTOF) to broadly profile pulmonary immunity induced by IV BCG and observed an expansion of CD69- NK cells characterized by expression of the cytotoxic molecule granzyme B but not IFN-γ in bronchoalveolar lavage. Flow cytometry experiments revealed that CD69- NK cell frequencies are increased in the lungs after IV BCG and associated with protection against Mtb challenge. An in vitro cytotoxicity assay revealed superior cytolytic capacity of CD69- NK cells compared to CD69 + NK cells derived from the lungs of IV BCG vaccinated macaques. Taken together, our data suggest that IV BCG induces the recruitment of CD69-granzyme B + NK cells to the lungs where they may contribute to protection via direct lysis of Mtb-infected cells. One Sentence Summary: Intravenous BCG vaccination induces the expansion of CD69- NK cells, which display enhanced cytotoxicity in-vitro and is associated with protection against tuberculosis.

The immune balance in mucosal tissues depends on a delicate interplay between inflammatory T helper 17 (Th17) cells and immunosuppressive regulatory T cells (Tregs). But what happens when this balance is disturbed? In this study, we uncovered a critical role for Acyl-CoA synthetase bubblegum family member 1 (Acsbg1) in shaping Th17 and Treg dynamics. Using Acsbg1-deficient mice, we show that while its absence does not disrupt homeostasis under steady-state conditions, it significantly alters Treg populations, particularly in gut-associated tissues. Under high-fat diet-induced metabolic stress, Acsbg1-deficient mice display mild metabolic changes but maintain systemic immune and metabolic function, indicating that Acsbg1 is dispensable for metabolic adaptation in vivo. However, upon infection with Citrobacter rodentium, these mice exhibit excessive Th1/Th17-driven inflammation and impaired resolution, accompanied by a strong reduction in IL-10-producing and ST2⁺ Treg subsets. The impact is even more striking in an adoptive transfer colitis model, where Acsbg1-deficient Tregs fail to control inflammation, resulting in severe colitis and tissue damage. Our findings identify Acsbg1 as a key regulator of ST2⁺ Treg function and a central player in mucosal immune homeostasis, highlighting its potential as a therapeutic target for inflammatory bowel disease and colorectal cancer.

Radiotherapy (RT) is essential in treating abdominal and pelvic cancers but often damages the healthy tissues, particularly the intestines, leading to radiation-induced toxicities with limited treatment options. While the immune system is known to help regulate tissue damage, immune mechanisms involved in RT-induced intestinal toxicity are not fully understood. Following CT-guided localised intestinal irradiation, single-cell RNA sequencing (scRNA-seq) and flow cytometry revealed RT-induced chemokine-dependent recruitment of innate immune cells. Deletion of C-C chemokine receptor (Ccr)1, Ccr2, Ccr3 and Ccr5, blocked recruitment and worsened radiation-induced toxicities, suggesting an important role for an innate immune cell population in limiting RT-mediated bowel damage. Furthermore, CCR2-deficient mice showed exacerbated weight loss and intestinal permeability, while the transfer of Ly6C⁺ monocytes alleviated symptoms. Mechanistically, IL-17 cytokine production by group 3 innate lymphoid cells (ILC3s), a critical factor in maintaining intestinal barrier integrity, was found to be reduced in irradiated CCR2^-/-, moreover the transfer of Ly6C⁺ monocytes resulted in increased IL-17 levels. These findings demonstrate the critical importance of CCR2-mediated monocyte recruitment in mitigating RT-induced toxicities. One Sentence Summary: CCR2-mediated monocyte recruitment protects against RT-induced intestinal toxicity via IL-17, highlighting a therapeutic target.

Xenobiotics and environmental factors implicated in inflammatory bowel disease (IBD) are metabolized by cytochrome P450 enzymes. Cyp2s1, an orphan member of this family, is highly expressed in the intestine, yet its role remains unclear. Here, we investigated the function of Cyp2s1 in intestinal homeostasis and inflammation by combining untargeted metabolomics, microbiome sequencing, colitis mouse models, and IBD patient biopsies. We observed markedly reduced Cyp2s1 expression in patients with active IBD and in multiple colitis models. Single-cell RNA sequencing identified abundant Cyp2s1 expression in the intestinal epithelium. Importantly, the AhR agonist, 6-Formylindolo[3,2-b]carbazole (FICZ) robustly induced Cyp2s1 expression in mouse colon organoids and Caco-2 cells. Mechanistically, metabolomic analysis of intestinal epithelial cells and feces from mice overexpressing or lacking Cyp2s1 revealed altered metabolite profiles. The SCENITH assay further confirmed disrupted fatty acid oxidation capacity in colonocytes of Cyp2s1-transgenic mice. Moreover, shotgun microbiome sequencing revealed reduced microbial richness and expansion of A. muciniphila in Cyp2s1-overexpressing mice. Consequently, upon DSS challenge, these mice developed exacerbated colitis symptoms compared to controls. Our findings identify Cyp2s1 as a novel AhR-inducible gene critical for modulating the intestinal metabolome and microbiome, suggesting that targeting AhR activity or Cyp2s1 itself may offer therapeutic strategies for IBD.

T follicular helper cells (T_FH) play a central role in orchestrating antibody mediated immunity. Despite the importance of antibody responses, especially allergen-specific IgE, in allergic airway diseases (AAD) such as asthma, the precise role T_FH play in AADs has remained elusive. Using a mouse model of chronic allergen induced AAD we now show that germinal centres (GCs) containing T_FH and GC B cells accumulate in both the lung draining lymph nodes (dLNs) and the lungs themselves after allergen exposure. The formation of these GCs is dependent on T_FH, as is generation of allergen specific IgA, IgG and IgE, with IgG1 and IgE-switched B cells being predominantly found in the dLNs while IgA switched B cells were only found in the lungs. Fitting with this, allergen-induced lung resident T_FH and B cells are functionally and transcriptionally distinct from their lymphoid counterparts, with lung GCs providing a unique site of IgA-switch, a process that is partially IL-17A dependent. Finally while T_FH deficiency did not worsen allergic airways disease after 3 weeks of aero-allergen exposure, worsened lung function and enhanced T_H2-based inflammation in the respiratory tract were seen following 5 weeks of exposure. Overall these data suggest that T_FH play a pivotal role in shaping immune responses both in the dLNs and the respiratory tract, and while they can promote key type-2 inflammatory pathways such as IgE production, they can also act to limit prolonged type-2 inflammation.