Mucosal Immunology最新文献

Paneth cells are secretory intestinal epithelial cells most abundant in the ileum that contribute to gut homeostasis and innate immunity through secretion of antimicrobial peptides and intestinal stem cell factors. Dysfunction of Paneth cells has been implicated in various gastrointestinal disorders. Although regulation of Paneth cell function by microbial signals has been well established, accumulating evidence highlights a pivotal role for cytokine networks in modulating Paneth cell activity. Cytokines such as Interferons (IFNs), Interleukin (IL)-9, IL-13, IL-17, IL-22, and tumor necrosis factor (TNF) influence diverse aspects of Paneth cell biology and, in turn, intestinal tissue homeostasis. In this review, we synthesize current knowledge of cytokine-mediated regulation of Paneth cells, explore the emerging role of Paneth cell phenotyping as predictive in intestinal disease outcomes, and conclude with key unanswered questions that define future research directions in the field.

Secondary bacterial pneumonia causes substantial morbidity and mortality following influenza A virus (IAV) infection, yet no therapies exist that address the underlying immune dysfunction and epithelial damage that predispose to bacterial superinfection. Here, we demonstrate that short-course intranasal treatment with LAT9997, a synthetic peptide derived from human growth hormone, protects against severe IAV infection and subsequent Streptococcus pneumoniae superinfection. Significantly, just two intranasal doses administered on days 1 and 2 post-IAV infection, with no further treatment, improved survival from 0% to 85%, reduced bacterial burden in the airways, and markedly attenuated lung pathology. Mechanistically, LAT9997 selectively suppressed epithelial AKT Ser473 phosphorylation, rebalancing infection-induced signalling to reduce viral dissemination, limit lung damage, and preserve barrier integrity during the viral phase. This early intervention established a protective airway immune environment characterized by preserved alveolar macrophages, restrained neutrophil recruitment, and reduced inflammatory mediators. During subsequent bacterial challenge, innate immune cells displayed phenotypic markers of controlled activation, including enhanced neutrophil viability, reduced inflammatory surface markers, and restrained protease activity, occurring without broad alterations in cell numbers. These findings provide proof-of-concept that brief, host-directed therapy during acute viral infection can durably prevent post-viral bacterial pneumonia by modulating lung immunity and preserving barrier integrity.

The mechanisms underlying innate lymphoid cell (ILC) development and function in the neonatal lung remain incompletely defined. ILCs are critical mediators of early-life innate immune responses in the lung. Dysregulation of ILC homeostasis has both immediate and long-lasting effects on lung health. We generated single-cell transcriptomic and epigenetic datasets from the lungs of neonatal and young adult mice that includes subsets of type 1 (natural killer, NK cells) type 2 (ILC2) and type 3 (ILC3) cells. These datasets include mice subjected to early life antibiotic-induced dysbiosis, thereby modeling a common perturbation of the developing immune system in humans. Analysis of cell-cell communication and gene regulation in these datasets reveals underappreciated aspects of lung ILC biology, including marked interleukin-4 (IL-4) signaling in neonatal lung ILC2. This data represents a valuable resource for hypothesis generation regarding the molecular regulation of ILC gene expression and function in the neonatal lung.

Lung-trafficking helminth larvae drive an early pulmonary neutrophilic inflammation prior to the establishment of the hallmark Type 2 immune response. While IL-11 is known to play crucial roles in chronic inflammatory responses, its role in the mucosal immunity to helminth parasites has not been assessed to date. In a mouse model for Ascaris infection, we observed elevated IL-11 levels in lung tissue that strikingly correlated with parasite burden. Single-cell molecular and phenotypic analyses, combined with confocal and RNAscope spatial imaging, identified lung epithelial cells and peribronchial stromal cells, including myofibroblasts and smooth muscle cells, as important sources of IL-11 in naïve and Ascaris-infected lungs. In the absence of IL-11 signaling, using IL-11Rα1-deficient mice infected with Ascaris, we noted a marked reduction in lung neutrophil influx and decreased levels of neutrophil-associated mediators (CXCL-1 and G-CSF). Conversely, intranasal administration of recombinant IL-11 induced high levels of G-CSF and CXCL-1 and enhanced mucosal inflammation in the lungs. To confirm direct effect of IL-11 in regulating neutrophil-associated markers we showed that in vitro stimulation with recombinant IL-11 drove IL-6 and G-CSF production in fibroblasts, and CXCL-1 in epithelial cells. These findings suggest that IL-11 acts as a pro-inflammatory mediator that orchestrates the early neutrophil-driven inflammation during acute helminth infection, unraveling a critical role of IL-11 in pathogenic inflammatory responses.

Silicosis is an inflammation-driven pulmonary fibrosis caused by occupational inhalation of silica particles. Macrophages are crucial in silicosis pathology, yet their interaction with stromal cells in orchestrating fibrosis progression remains poorly understood. Single-cell RNA sequencing (scRNAseq) of whole-lung lavages from silicosis patients identified the expansion of an intermediate CCL2-hi monocyte-like macrophage (MLM) cluster that further differentiated into inflammatory IL1B-hi and pre-fibrotic SPP1-hi (osteopontin) subsets. SPP1-hi MLMs showed enrichment for tissue remodelling (SPP1, CHI3L1, MMP14, COL6A1), oxidative stress (GCLC, TXN, PRDX1), and bio-mineralisation genes (GLA, CA2, CTSK). To explore immune-stromal dynamics, we developed a site-specific silicosis mouse model with a miniture bronchoscope. Mouse scRNAseq analysis and cell-cell communication modelling identified novel neutrophil subsets, reprogrammed alveolar type 2 epithelial cells, and two Sfrp1-hi/Spp1-hi fibroblast subsets involved in crosstalk with MLMs. These data identify key components of the silicotic niche and predict targetable interactions within the immune-stromal axis for ameliorating disease.

T cells play a central role in host protection against respiratory pathogens, but a maladaptive T cell response can lead to pulmonary diseases. Previous studies have examined T cells from the lungs captured via bronchoalveolar lavage (BAL), endobronchial brushings, or biopsies. However, whether these different approaches are capturing distinct T cell phenotypes and/or clonotypes remains unclear. Here, using single cell RNA- and T cell receptor (TCR)-sequencing, we report unique phenotypes and clonotypes of T cells isolated via BAL versus endobronchial brushings in healthy controls (HCs) and allergic asthmatics (AAs). The most significant difference in T cell subset abundance between AAs and HCs was the enrichment of CD4 T helper type 2 (T_H2) cells when comparing endobronchial brush samples (OR = 20.8, P = 0.004), but not when examining BAL (OR = 1.8, P = 0.38), indicating differences in the T cell subsets captured from the BAL versus airway mucosa. In further support of this observation, comparing the BAL and brush T cells across all subjects revealed an up-regulation of resident-memory T (T_RM) cell markers (i.e. ITGAE, CD69) in brush T cells in both CD4 and CD8 lineages. In contrast, BAL CD8 and CD4 T cells exhibited an enriched type I and II interferon signature compared to brush T cells. We validated these findings by generating an independent cohort from publicly available single cell RNA-sequencing data of BAL and brush T cells. Lastly, leveraging the paired samples from our derivation cohort, we performed TCR repertoire analysis, revealing that brush T cells contained expanded TCR clones that were in low abundance or absent in the BAL. Expanded T cell clones from the brush expressed high levels of T_RM cell markers, suggesting the airway mucosa is enriched for T_RM cells with unique TCR specificity. In sum, sampling T cells via BAL versus airway brushings yielded distinct T cell phenotypes and clonotypes with important implications for future research in lung immunology.

Type 2 cytokinerelease promotes wound healing and helminth clearance, but it remains unclearwhethergroup 2 innate lymphocytes (ILC2s) and T-helper2 cells (T_H2) cells have functionally distinctroles during anamnestic immunity. This study demonstrates that ILC2 can prevent re-infection andlimit tissue injury caused by the helminthNippostrongylus brasiliensis (Nb). T_H2 cells were necessary during initial antigen encounter but dispensable forearly pathogen clearance and lungrepairafterILC2 priming. Upon re-infection, trained ILC2 selectively blocked interleukin (IL)-17+ γδT cell expansion and infection-induced lung injury through an Amphiregulin (Areg)-independent mechanism. Trained ILC2s had a distinct metabolic gene expression profile marked by elevated tryptophan hydroxylase 1(Tph1) and pulmonary serotonin levels were largely ILC2-dependent. Surprisingly, serotonin prevented IL-17-associated lung hemorrhage irrespective of parasite load. We propose that T_H2-ILC2 interactions drive pathogen control, but ILC2 distinctly control lung tissuerepairthrough serotonin.

The intestinal epithelium undergoes robust maturation postnatally, yet its early-life characteristics remain poorly understood. Using single-cell RNA sequencing, we analyzed intestinal epithelial cells from neonatal (10-day-old) and juvenile (21-day-old) mice reared under both specific pathogen-free and germ-free conditions. Among the various cell types comprising the intestinal epithelia, we found that enterocytes, in particular, exhibit markedly different features between these stages. Enterocytes of neonatal mice show reduced expression of secretory host defense-related genes independently of microbial colonization. These genes are upregulated in juvenile enterocytes in a microbiota-independent manner. Conversely, neonatal enterocytes display upregulation of ketogenesis-related genes, which correlates with high expression of genes contributing to cell morphogenesis rather than serving primarily as an energy source. These findings provide novel insights into early-life maturation of intestinal epithelia offering implications for understanding neonatal intestinal pathologies.

Regulatory T (Treg) cells are well recognized for their role in immune regulation; however, their role in tissue regeneration is not fully understood. This study demonstrates such a role of Tregs in a published preclinical murine model of spontaneous pulmonary fibrosis (PF) expressing a human PF related mutation in the Surfactant Protein-C (SP-C) gene (SFTPC^I73T). Genetic crosses of SP-C^I73T mice with Foxp3^GFP and Foxp3^DTR lines were utilized to study Treg behavior during PF development. We found that FoxP3+ Tregs accumulate during the transition from inflammation to fibrogenesis, peaking at 21-28 days after mutant Sftpc^I73T induction localizing to both perivascular and distal fibrotic lung regions. Diphtheria toxin mediated ablation of Tregs at 17 days worsened fibrosis and increased levels of TGFβ and inflammatory cytokines. Tregs expressed Th2 markers (Gata3+) and elaborated factors including amphiregulin (Areg) and Osteopontin (Spp1). Reductionist experiments showed that lung Tregs enhanced organoid formation when co-cultured with alveolar epithelial cells and adventitial fibroblasts, an effect size mimicked using Areg and Spp1 in combination. Our findings demonstrate that immune-mesenchymal-epithelial signaling crosstalk is present in the distal lung wherein Tregs play a protective role by limiting fibrosis and promoting tissue repair, highlighting their broader function beyond immune modulation in lung injury.

Reduced dietary fiber intake is associated with, and may have contributed to, the post-mid-20th century increase in immune-mediated chronic inflammatory diseases, including inflammatory bowel disease (IBD). Reduced fiber intake has resulted, in part, from increased consumption of highly refined foods including those made from white flours, generation of which involves removal of much of the fiber naturally present in wheat kernels. Accordingly, we hypothesized that wheat fiber (WF) might protect against chronic inflammatory diseases. We tested this notion in a murine T-cell-transfer colitis model. Rag1^-/- mice were fed purified (open-source) low-fiber diets enriched, or not, with WF and then administered CD45Rb^hi T-cells. WF conferred robust protection in this colitis model as assessed by an array of clinical, histopathologic, morphologic, and immune-related parameters. WF's protection against colitis associated with a microbiota-dependent increase in Foxp3⁺ T-cells (Tregs), which could be recapitulated in vitro. WF did not induce Tregs in mice lacking conserved non-coding sequence 1 knock-out (CNS1), which is known to drive peripheral Treg development, nor did WF protect against T-cell-transfer colitis driven by transplant of colitogenic T-cells from CNS1^-/- mice. Thus, enriching diet with WF has potential to promote microbiota-dependent peripheral Treg development and, consequently, protect against chronic inflammatory diseases.