Mucosal Immunology最新文献

Natural Killer (NK) cells are cytotoxic lymphocytes and key mediators of innate immunity, essential for combating viral infections and cancer. Notably, they exhibit immunological memory, generating a stronger response upon re-exposure to the same stimulus. While NK cell memory holds promise for infection control, its role in bacterial infections remains poorly understood. Previously, we demonstrated that Streptococcus pneumoniae induces long-term, specific, and protective NK cell memory. In this study, we performed single-cell RNA-seq to uncover how NK cells respond to S. pneumoniae infection. Our findings reveal that challenged Memory (cMemory) NK cells undergo transcriptional reprogramming following S. pneumoniae infection and have a differential transcriptional response upon reinfection. In addition, we identified distinct cMemory NK cell subpopulations, with responding cMemory NK cells displaying a general enhanced activation, proliferation, and cytotoxic activity. These findings support a novel role for NK cells in the context of bacterial infections, thereby opening avenues for harnessing the potential of innate immune memory for therapeutic applications.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract. It is characterised by epithelial and immunological dysfunctions, including alterations in populations of Innate Lymphoid Cells (ILCs), including tissue-resident RORγt-expressing Group 3 ILCs (ILC3s). ILC3s contribute to the maintenance of intestinal homeostasis by closely interacting with both the epithelium and adaptive immune cells. Here, we reveal that murine and human ILC3s modulate these interactions through Transforming Growth Factor-Beta 1 (TGF-β1), a pleiotropic cytokine secreted in an inactive form. We show that ILC3s synthesise and activate latent TGF-β1 through mechanical and proteolytic pathways. ILC3s aid the induction of FoxP3⁺ regulatory T cells via TGF-β1 and promote a regenerative transcriptional signature in intestinal epithelial cells. The downstream impact of ILC3-derived TGF-β1 is conserved between mouse and humans, but the TGF-β1 activators expressed by ILC3 differ between the species. In IBD, where ILC3s are reduced in the inflamed intestinal regions, TGF-β1-production and activation machinery remains intact in ILC3s, suggesting this pathway is functional in disease and could be targeted to enhance intestinal homeostasis through promotion of epithelial regeneration and induction of regulatory T cells.

Germinal centres (GCs) in mucosal tissues such as the nasal associated lymphoid tissue (NALT) generate high-affinity antibodies critical for protective, and in some cases, sterilising immunity. Therefore, initiation of GCs at the respiratory mucosa is of tremendous clinical significance in the development of mucosal vaccines. However, GC initiation in NALT is limited in part by a scarcity of CD4⁺ T follicular helper (T_FH) cells, and the tolerogenic environment in the NALT. Here, we identify a critical role for Natural Killer T (NKT) cells with a follicular helper-like phenotype (NKT_FH) in driving NALT GC formation. Unlike their systemic counterparts, mucosal NKT cells evade anergy after repeated stimulation and remain poised to provide early cognate B cell help to CD1d-presented antigens. We show that NKT_FH provide IL-21, allowing for GC recruitment and functionally substituting for a pre-expanded CD4⁺ T_FH pool. These findings reveal a previously unrecognised NKT-dependent mechanism of GC seeding in the NALT and suggest that inclusion of an NKT cell agonist into intranasal vaccines could overcome GC entry bottlenecks and enhance high-affinity antibody responses.

We have previously demonstrated that the circadian clock regulates the host response to influenza A virus (IAV) infection. While IL-10 is well-known for its immunoregulatory function, its role in IAV remains unclear, with studies reporting both protective and detrimental effects. Given the diurnal rhythmicity of IL-10 receptor (IL-10ra) expression in the lung, we investigated the contribution of IL-10 signaling to time-of-day-specific IAV protection. We found that blocking IL-10 signaling abrogated the time-of-day protection, leading to increased immunopathology characterized by enhanced lymphocyte infiltration and global immune activation (transcriptomic analysis). Interestingly, while later, IL-10R blockade also eliminated the time-of-day difference in IAV outcomes, it improved the outcome of dusk-infected mice. Furthermore, Natural Killer (NK) cell depletion suppressed IL-10 levels in bronchoalveolar lavage, suggesting a role for these cells in regulating IL-10 signaling. In conclusion, incorporating the circadian context has not only clarified the IL-10 role in IAV infection but also underscored the pivotal influence of circadian regulation on immune responses.

Seminal fluid elicits an immune response in the uterine mucosa after mating that impacts embryo implantation and pregnancy, but the underlying molecular and cellular events are unclear. In this study, we report RNA sequencing to analyze the uterine response to seminal fluid after mating. Females exposed to seminal fluid of intact males exhibited gene expression changes on D3.5 post-coitum (pc) just prior to embryo implantation, compared to females mated with males surgically rendered seminal plasma deficient. Functional enrichment analysis revealed genes related to T cell activation amongst those with the largest fold-changes. Using flow cytometry we then showed profound changes in uterine T cell abundance and phenotype regulated by seminal fluid contact. While CD4⁺ and CD8⁺ T cells were elevated by seminal fluid, the most conspicuous change was in CD4^-CD8^- T cells expressing γδ T cell receptors (TCR). Mating with intact males caused a 8.3-fold increase in γδ T cell abundance compared to estrous virgin females, and a 22.4-fold increase in the proportion of γδ T cells expressing proliferation marker Ki67. Vγ6⁺ cells were the most abundant subpopulation in the uterus, followed by Vγ4⁺ and Vγ1⁺ T cells, and all three were similarly expanded after mating. Seminal plasma was critical for γδ T cell accumulation and activation in the endometrium, and similar changes occurred in uterine-draining lymph nodes but not spleen. These findings identify γδ T cells as prominent in the immune response to seminal fluid and imply key roles in uterine immune regulation and reproductive success.

Airborne fungi are potent inducers of respiratory disease and cause the debilitating conditions severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis (ABPA). However, the immune cell types and the inflammatory airway environment that defines SAFS and ABPA patients is not extensively characterised. To address this, we recruited SAFS and ABPA patients, asthmatics without evidence of fungal sensitisation and healthy controls (n = 20 individuals per group). Immune cells were isolated from collected sputum and peripheral blood samples and immunophenotyping was performed via flow cytometry. By applying a machine learning approach to our dataset, we identify a critical association between CD4⁺ T cells, type 2 conventional dendritic cells, eosinophils, proinflammatory factors and severe respiratory disease. These complex immune signatures should be investigated further to improve the diagnostics and treatment of SAFS and ABPA.

The mucosal immune system plays a fundamental role in maintaining microbial balance. Microbial imbalance in the female genital tract increases the risk for adverse health outcomes in women and may increase susceptibility to local infections. Myeloid-derived suppressor cells (MDSCs) remain understudied in the context of female genital tract conditions. Here we show that frequency of polymorphonuclear (PMN-) MDSCs increased in the cervical mucosa of women with Chlamydia trachomatis infection, bacterial vaginosis, or with a coinfection, but not in women with human papillomavirus infection. Mucosal PMN-MDSC frequencies correlated with mucosal IL-1β in C. trachomatis patients and ex vivo exposure of cervical tissue to C. trachomatis elevated both PMN-MDSC frequencies and IL-1β secretion. Likewise, exposure of cervical tissue to cervicovaginal lavage fluid from C. trachomatis and bacterial vaginosis patients also enhanced PMN-MDSC frequencies. Lastly, cervical MDSCs expressed suppressive mediators and functionally suppressed cytotoxic T-cell responses. Our study identifies IL-1β-stimulated PMN-MDSCs as immunosuppressive mediators in female genital tract infections, potentially modulating susceptibility to local secondary infections.

Macrophages are crucial for the maintenance of intestinal homeostasis, are considered key proinflammatory effector cells during intestinal inflammation and are implicated in tissue repair following injury or inflammation. Whether these roles are attributed to distinct subsets of macrophages or if macrophages retain a degree of plasticity in the intestine remains poorly understood. Here, through a combination of single cell RNA sequencing, lineage-tracing and immunofluorescence imaging, we define three major subpopulations of murine, colonic macrophages on the basis of CD11c and CD163 expression. These macrophages occupy discrete anatomical niches and display distinct replenishment kinetics. They all accumulate during acute colitis and Cx3cr1--based fate mapping shows that they persist through to inflammation resolution. Moreover, marked transcriptional differences exist between the macrophages present in health and their counterparts in the post-inflammation environment, demonstrating that inflammation leads to transcriptional rewiring of the resident macrophages in a subset-specific manner. Intriguingly, there were minimal transcriptional changes between long-lived macrophages and their recently differentiated counterparts, indicating the environment exerted a greater influence than ontogeny or the time of residency on their functional states in inflammation resolution.