Mucosal Immunology最新文献

Immunoglobulin A (IgA), the most abundantly produced antibody at mucosal surfaces, is thought to play key roles in immune responses to respiratory and enteric pathogens and in the regulation of commensal colonization. Low IgA levels have been associated with recurrent infections and immune dysregulation, including inflammatory bowel disease and autoimmunity. Levels of IgA in maternal breast milk and infant stool are both inversely associated with the emergence of immune responses to food antigens in infants and, in naturally resolving food sensitivity and immunotherapy protocols, the induction of IgA antibodies to dietary antigens has been associated with the acquisition of food tolerance. Here, we uncover new roles for IgA in intestinal immune homeostasis utilizing IgA Knockout (KO) mice generated by CRISPR/Cas9. IgA-deficient mice exhibit hyperimmunoglobulinemia, with increased levels of IgE and MCPT-1. The hyperimmunoglobulinemia is associated with dysregulated Tfh/Tfr responses in the Peyer's Patches (PPs) and spontaneous immunoglobulin production to chow diet. These findings shed light on important interactions between IgA, the mucosal immune system, and the regulation of Tfh responses, emphasizing the importance of IgA in maintaining immune homeostasis at mucosal surfaces.

Mucosal tissues, including those in the respiratory and gastrointestinal tracts, are critical barrier surfaces for pathogen invasion. Infections at these sites not only trigger local immune response, but also recruit immune cells from other tissues. Emerging evidence in the mouse models and human samples indicates that the immune crosstalk between the lung and gut critically impacts and determines the course of respiratory disease. Here we summarize the current knowledge of the immune crosstalk between the respiratory and gastrointestinal tracts, and discuss how immune cells are recruited and migrate between these tissues during respiratory infections. We also discuss how commensal bacteria contribute to these processes.

Diabetes mellitus is associated with an increased risk of pneumonia, often caused by so-called typical and atypical pathogens including Streptoccocus pneumoniae and Legionella pneumophila, respectively. Here, we employed a variety of mouse models to investigate how diabetes influences pulmonary antibacterial immunity. Following intranasal infection with S. pneumoniae or L. pneumophila, type 2 diabetic and prediabetic mice exhibited higher bacterial loads in their lungs compared to control animals. Single cell RNA sequencing, flow cytometry, and functional analyses revealed a compromised IFNγ production by natural killer cells in diabetic and prediabetic mice, which was associated with reduced IL-12 production by CD103⁺ dendritic cells. Blocking IFNγ enhanced susceptibility of non-diabetic mice to L. pneumophila, while IFNγ treatment restored defense against this intracellular pathogen in diabetic animals. In contrast, IFNγ treatment did not increase resistance of diabetic mice to S. pneumoniae, suggesting that impaired IFNγ production is not the sole mechanism underlying the heightened susceptibility of these animals to pneumococcal infection. Thus, our findings uncover a mechanism that could help to explain how type 2 diabetes predisposes to pneumonia. We establish proof of concept for host-directed treatment strategies to reinforce compromised IFNγ-mediated antibacterial defense against atypical lung pathogens.

Inflammatory bowel diseases (IBDs) are characterized by unrestrained innate and adaptive immune responses and compromised intestinal epithelial barrier integrity. Regulatory T (T_reg) cells are crucial for maintaining self-tolerance and immune homeostasis in intestinal tissues. Prostaglandin E₂ (PGE₂), a bioactive lipid compound derived from arachidonic acid, can modulate T cell functions in a receptor subtype-specific manner. However, whether PGE₂ regulates T_reg cell function and contributes to IBD pathogenesis remains unclear. Here, we found that the PGE₂ receptor subtype 2 (EP2) is highly expressed in T_reg cells. T_reg cell-specific deletion of EP2 resulted in increased T_reg cell numbers, and enhanced granzyme B(GzmB) expression and immunosuppressive capacity of T_reg cells in mice. Adoptive transfer of EP2-deficient T_reg cells attenuated naïve CD4⁺ T cell transfer-induced colitis in Rag1^-/- mice. Mice with EP2-deficient T_reg cells were protected from 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colitis. Pharmacological blockage of EP2 with PF-04418948 markedly alleviated DSS-induced colitis in mice in a T_reg-dependent manner. Mechanistically, activation of EP2 suppressed T_reg cell function, at least in part, through reduction of GzmB expression via PKA-mediated inhibition of NF-κB signaling. Thus, we identified the PGE₂/EP2 axis as a key negative modulator of T_reg cell function, suggesting EP2 inhibition as a potential therapeutic strategy for IBD treatment.

Neuro-immune interactions within barrier organs, such as lung, gut, and skin, are crucial in regulating tissue homeostasis, inflammatory responses, and host defence. Our rapidly advancing understanding of peripheral neuroimmunology is transforming the field of barrier tissue immunology, offering a fresh perspective for developing therapies for complex chronic inflammatory disorders affecting barrier organs. However, most studies have primarily examined interactions between the peripheral nervous system and the immune system from a neuron-focused perspective, while glial cells, the nonneuronal cells of the nervous system, have received less attention. Glial cells were long considered as mere bystanders, only supporting their neuronal neighbours, but recent discoveries mainly on enteric glial cells in the intestine have implicated these cells in immune-regulation and inflammatory disease pathogenesis. In this review, we will highlight the bi-directional interactions between peripheral glial cells and the immune system and discuss the emerging immune regulatory functions of glial cells in barrier organs.

The precise role of neutrophil-derived reactive oxygen species (ROS) in combating bacterial uropathogens during urinary tract infections (UTI) remains largely unexplored. In this study, we elucidate the antimicrobial significance of NADPH oxidase 2 (NOX2)-derived ROS, as opposed to mitochondrial ROS, in facilitating neutrophil-mediated eradication of uropathogenic Escherichia coli (UPEC), the primary causative agent of UTI. Furthermore, NOX2-derived ROS regulate NF-κB-mediated inflammatory responses in neutrophils against UPEC by inducing the release of nuclear factor erythroid 2-related factor 2 (Nrf2) from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1). Consistently, the absence of NOX2 (Cybb^-/-) in mice led to uncontrolled bacterial infection associated with increased NF-κB signaling, heightened neutrophilic inflammation, and increased bladder pathology during cystitis. These findings underscore a dual role for neutrophil NOX2 in both eradicating UPEC and mitigating neutrophil-mediated inflammation in the urinary tract, revealing a previously unrecognized effector and regulatory mechanism in the control of UTI.

The murine uterus contains three subsets of innate lymphoid cells (ILCs). Innate lymphoid cell type 1 (ILC1) and conventional natural killer (cNK) cells seed the uterus before puberty. Tissue-resident NK (trNK) cells emerge at puberty and vary in number during the estrous cycle. Here, we addressed the origin of uterine trNK cells and the influence of ovarian hormones on their local activation and differentiation in vivo. We used parabiosed mice in combination with intravascular fluorescent antibody labeling and flow cytometry to distinguish tissue-resident from circulating immune cells. Additionally, we used C57BL/6J ovariectomized (OVX) and non-OVX mice supplemented with ovarian hormones to assess their effects on uterine trNK cell function. Strikingly, mice OVX at three weeks of age and analyzed as adults lacked uterine trNK cells unless progesterone was administered. Our parabiosis studies confirmed that the progesterone-responsive trNK cells are derived from peripheral cNK cells. Moreover, medroxyprogesterone 17-acetate-induced expansion of cNK-derived trNK cells was abolished by a progesterone receptor antagonist. These data reveal a novel, uterine-specific differentiation pathway of trNK cells that is tightly regulated by progesterone.

Decidual CD8⁺T (dCD8⁺T) cells are pivotal in the maintenance of the delicate balance between immune tolerance towards the fetus and immune resistance against pathogens. The endometrium and decidua represent the uterine environments before and during pregnancy, respectively, yet the composition and phenotypic alterations of uterine CD8⁺T cells in these tissues remain unclear. Using flow cytometry and analysis of transcriptome profiles, we demonstrated that human dCD8⁺T and endometrial CD8⁺T (eCD8⁺T) cells exhibited similar T cell differentiation statuses and phenotypes of tissue infiltrating or residency, compared to peripheral CD8⁺T (pCD8⁺T) cells. However, dCD8⁺T cells showed decreased expression of coinhibitory marker (PD-1), chemotaxis marker (CXCR3), and tissue-resident markers (CD69 and CD103), along with increased expression of granzyme B and granulysin, compared to eCD8⁺T cells. In vitro cytotoxicity assays further demonstrated that dCD8⁺T cells had greater effector functions than eCD8⁺T cells. Additionally, both in vitro and in vivo chemotaxis assays confirmed the recruitment of non-resident effector memory T cell subsets to the pregnant decidua, contributing to the dCD8⁺T cell-mediated anti-infection mechanism at the maternal-fetal interface. This work demonstrates dCD8⁺T cells replenished from the circulation retain their cytotoxic capacity, which may serve as an enhanced defense mechanism against infection during pregnancy.

Despite the central role of cytokines in mediating inflammation that underlies a range of childhood diseases, cytokine testing remains primarily limited to research settings and surrogate markers of inflammation are often used to inform clinical diagnostic and treatment decisions. There are currently no reference ranges available for cytokines in healthy children, either systemically (in blood) or at sites of disease (such as the lung). In our study, we aimed to develop an openly accessible dataset of cytokines in the airways and blood of healthy children spanning 1 to 16 years of age. We examined how cytokine concentration changes during childhood and assessed whether a core set of cytokine markers could be used to indirectly evaluate the response of a broad spectrum of inflammatory analytes. To develop our dataset, a total of 65 unique analytes were quantified in cell-free bronchoalveolar lavage (BAL) and plasma from 78 children. We showed that age profoundly impacts soluble immune analyte concentration in both sample types and identified a highly correlative core set of 10 analytes in BAL and 11 analytes in plasma capable of indirectly evaluating the response of up to 44 inflammatory mediators. This study addresses an urgent need to develop reference ranges for cytokines in healthy children to aid in diagnosis of disease, to determine eligibility for, and to monitor the effects of, cytokine-targeted monoclonal antibody therapy.

We aimed to elucidate the dynamic changes in short-chain fatty acids (SCFA) produced by the gut microbiota following smoking exposure and their role in chronic obstructive pulmonary disease (COPD) pathogenesis. SCFA concentrations were measured in human plasma, comparing non-smokers (n = 6) and smokers (n = 12). Using a mouse COPD model induced by cigarette smoke exposure or elastase-induced emphysema, we modulated SCFA levels through dietary interventions and antibiotics to evaluate their effects on inflammation and alveolar destruction. Human smokers showed lower plasma SCFA concentrations than non-smokers, with plasma propionic acid positively correlating with forced expiratory volume in 1 s/forced vital capacity. Three-month smoking-exposed mice demonstrated altered gut microbiota and significantly reduced fecal SCFA concentrations compared to air-exposed controls. In these mice, a high-fiber diet increased fecal SCFAs and mitigated inflammation and alveolar destruction, while antibiotics decreased fecal SCFAs and exacerbated disease features. However, in the elastase-induced model, fecal SCFA concentration remained unchanged, and high-fiber diet or antibiotic interventions had no significant effect. These findings suggest that smoking exposure alters gut microbiota and SCFA production through its systemic effects. The anti-inflammatory properties of SCFAs may play a role in COPD pathogenesis, highlighting their potential as therapeutic targets.