International immunology最新文献

The respiratory mucosa, encompassing the lungs and nasal tissues, serves as the primary barrier against respiratory viruses. While neutralizing antibodies are effective at preventing viral entry, virus-specific CD8⁺ T cells play a vital role in eliminating infected cells and inducing an antiviral state, which curbs disease progression. Among these, CD8⁺ tissue-resident memory T (TRM) cells persist long-term in the lungs, where they serve as first responders and rapidly expand upon secondary respiratory virus infection to provide local protection. The establishment and maintenance of lung CD8⁺ TRM cells require not only local cytokine signals but also antigen presentation. Specific subsets of antigen-presenting cells, such as dendritic cells, alveolar macrophages, monocytes, and endothelial cells also influence the quality and durability of CD8⁺ TRM cell responses. This review summarizes key findings on CD8⁺ T-cell dynamics during respiratory viral infections, with a particular focus on CD8⁺ TRM-cell formation and function. We also highlight the importance of local antigen presentation in driving TRM development and discuss how this knowledge can inform vaccine strategies aimed at eliciting robust, long-lasting mucosal immunity.

The aim of this study was to elucidate the effect of interleukin (IL)-35 on T-cell differentiation and its mechanism. We evaluated the therapeutic effect of IL-35 on acute respiratory distress syndrome using clinical samples and the mouse cecum ligation and puncture model. The effects of IL-35 on regulatory T cells (Tregs) were verified by flow cytometry, immunohistochemistry, and quantitative real-time reverse transcription polymerase chain reaction. Liquid chromatography-mass spectrometry was used to detect the effects of IL-35 on changes in glutamine metabolites and tricarboxylic acid (TCA) circulation. Western blot was used to detect changes in forkhead box protein 3 (Foxp3), key enzymes, and signal transducer and activator of transcription (STAT) phosphorylation subgroup proteins in the presence of cerdulatinib. Finally, A549 cells were treated with EL-4 cell supernatant to explore the effect of cerdulatinib on the therapeutic effect of IL-35 injury. Inflammatory factors decreased, and Foxp3 increased in response to IL-35. In addition, Foxp3 was upregulated in a glutamine-deficient environment, and notably, glutamine-related metabolism and TCA cycle-related substances were altered with the involvement of IL-35. IL-35 upregulated phosphorylation of STAT isoforms, and cerdulatinib reversed it. Finally, the effects of IL-35 on Foxp3, key enzymes, and glutamine metabolite changes were all reversed by cerdulatinib. Our study shows that IL-35 reduces lung inflammation and promotes Treg differentiation. IL-35 affects the glutamine metabolism and the TCA cycle. In addition, we demonstrated that the relevant functions of IL-35 may be mediated by STAT isoform phosphorylation.

The human gastrointestinal tract is a unique mucosal barrier with a tremendous surface area that is subject to continuous exposure to the environment. The immune system must remain poised to protect this organ system from potential pathogens while restraining chronic inflammatory responses that negatively impact physiological functions or facilitate malignancy. Innate lymphocytes emerged as major regulators of gut health through numerous key functions. Recent evidence indicates that these cells are adaptably influenced by specialized microniches, or distinct aggregates of cells that engage in dynamic crosstalk at a microscopic level and integrate signals from the environment to perform specialized functions with regional precision. Here we explore our current understanding of how microniches in the gut shape the biology of innate lymphocytes, with a focus on an interplay of diet and microbial exposure, selective cell-cell communication networks, and spatiotemporal properties. We also discuss how these microniches may be altered in human diseases or could be harnessed to better protect the gut. Finally, we identify current gaps in knowledge in this rapidly emerging field.

Fasting is known to alter the circulation dynamics of immune cells, including T cells, by shifting them from peripheral tissues to the bone marrow (BM), where they enter a quiescent state to avoid starvation stress and acquire apoptosis resistance through upregulation of BCL2. Upon refeeding, these T cells exit the BM and return to circulation. In solid tumors, fasting-refeeding not only affects the trafficking of CD8+ T cells between tumors and their draining lymph nodes (dLNs); but also modulates the antitumor immune response. In this study, we investigated how metformin's antitumor responses are affected by repeated fasting-refeeding cycles. Metformin administration combined with weekly 48-hour fasting showed a synergistic antitumor effect, which was abolished by in vivo depletion of CD8+ T cells. Immunohistofluorescence staining showed that fasting reduced CD8+T cells in tumors and dLNs while increasing their presence in the BM; refeeding reversed this distribution. Refeeding also increased the expression of Ifng, Gzmb, Tnf, and Tbx21 in tumors. Likewise, Cxcr6, Cxcl16, and Vcam1 expression levels were elevated only upon refeeding. Notably, CXCR6 was exclusively expressed on CD62L- effector memory T cells (TEM). The antitumor effect induced by the combinational therapy was abolished by administration of an anti-VCAM-1 neutralizing antibody. Our findings demonstrate that combining metformin with fasting exerts a synergistic antitumor effect by recruiting CD8+ T cells-relocated to the BM during fasting-back to the tumor during refeeding, facilitated by enhanced VCAM-1 expression on normalized tumor vasculature.

We previously identified Alcaligenes as symbiotic bacteria residing within Peyer's patches and demonstrated that their primary components, lipopolysaccharides, and their active center, lipid A, are excellent adjuvants for mucosal vaccination. Here, we evaluated the effectiveness of Alcaligenes-derived lipid A as an adjuvant for sublingual immunization, a novel vaccination route. Mice sublingually immunized with Alcaligenes lipid A and ovalbumin (OVA) showed enhanced production of OVA-specific IgA in both the respiratory and gastrointestinal tracts. In addition, increased serum levels of OVA-specific and IgG antibodies were elicited through germinal center reactions in the draining lymph nodes without excessive inflammation at the administration sites. These results demonstrated superior efficacy not previously achieved through other routes of administration (e.g., intranasal, subcutaneous, intramuscular administration) or by existing adjuvants (e.g., CpG-ODN). In addition, sublingual immunization with cholera toxin B subunit (CTB) and lipid A led to an elevated CTB-specific IgG response in the systemic compartment and an elevated IgA response in the intestinal tract, effectively suppressing the diarrhea induced by oral challenge with cholera toxin. Furthermore, immunization with pneumococcal surface protein A (PspA) plus Alcaligenes lipid A elicited strong PspA-specific CD4+ T cell proliferation and Th17 responses, as well as IgA and IgG responses, in both the respiratory tract and the systemic compartment. These effects enhanced pneumococcal clearance in the lungs and subsequent protection against Streptococcus pneumoniae infection. Together, our findings suggest that Alcaligenes-derived lipid A is a potent sublingual vaccine adjuvant with potential efficacy against both respiratory and intestinal infectious diseases.

In a typical immune response, naïve B cells are activated, differentiate into short-lived plasma cells (SLPCs), and then mature into long-lived plasma cells (LLPCs) in the bone marrow. Among three TNF family receptors (BAFF-R, TACI, and BCMA), BAFF-R and BCMA are known to be crucial for the maintenance of naïve B cells and bone marrow LLPCs, respectively. In contrast, the function of TACI remains unclear, as analysis of global TACI knockout mice suggests the existence of two opposing roles in B and plasma cells. Here, to define the role of TACI during T-dependent (TD) immune responses in a B and plasma cell-intrinsic manner, we utilized adoptive transfer experiments employing B cells with a conditional TACI knockout. We show that B cell activation is apparently normal in the absence of TACI, while it is crucial for the expansion of IgM+ and IgG1+ SLPCs and maintenance of their resultant bone marrow LLPCs. Hence, our data suggest that the hyper-B cell activation seen in global TACI knockout mice could be due to an indirect control of BAFF levels or B cell extrinsic anomalies.

Biliary tract cancer (BTC) exhibits a poor prognosis and limited responses to current therapeutic strategies. While surgical resection followed by adjuvant S-1 therapy is the standard curative treatment for BTC, long-term postoperative remission is hardly achieved. Therefore, more effective perioperative strategies are urgently needed. Here, we show that an immune-cold tumor microenvironment (TME) in KRAS-mutated BTC correlated with resistance to postoperative adjuvant S-1 therapy. Surgically resected tumor specimens were collected from 31 BTC patients who received adjuvant S-1 therapy after surgery and were subjected to integrated immunogenomic analysis, including multiplexed immunohistochemistry staining and whole-exome sequencing. The analysis revealed a strong correlation between limited CD8⁺ T cell and antigen-presenting cell (APC) infiltration into the TME and KRAS mutations in BTC. In addition, the distances between tumor cells and APCs, as well as between APCs and CD8⁺ T cells, were significantly greater in the TME of KRAS-mutated BTC than in that of KRAS wild-type BTC. These findings indicate that interactions between effector T cells and APCs were impaired in the TME of KRAS-mutated BTC, thereby disrupting antitumor immune responses. Furthermore, wild-type KRAS and abundant CD8⁺ T cells and APCs correlated with a favorable prognosis following adjuvant S-1 therapy for BTC. Altogether, we propose a novel immunogenomic-based biomarker for optimizing perioperative chemotherapy for BTC.

The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) regulates various cellular processes, including immune responses. Previous studies have demonstrated that mTORC1 plays a crucial for B cell differentiation and the production of IgM and IgG antibodies in response to foreign antigens. However, its role in steady-state antibody production remains poorly understood. In this study, we found that RaptorB-/- mice, which have a B cell-specific deletion of Raptor (an essential component of mTORC1), retained gut-associated IgA production. Conversely, IgM and IgG subclasses were virtually absent due to the loss of peripheral IgM+ mature B cells. We also found that IgA-producing cells were driven by the gut microbiota and were primarily localized in the intestinal lamina propria of RaptorB-/- mice. Consistently, IgA produced in RaptorB-/- mice was functional in its ability to bind gut bacteria and contributed to maintaining gut microbiota α-diversity, although its repertoire was restricted compared with that of control mice. Our findings demonstrated a distinct population of IgA-producing cells that develop independently of mTORC1 and contribute to gut homeostasis, thereby distinguishing them from conventional IgM- and IgG-producing cells.

Cells of the innate immune system, specifically group 2 innate lymphoid cells (ILC2s), play an important role in type 2 inflammation. However, their involvement in allergic rhinitis remains unclear. Thus, in this study, we aimed to clarify the role of ILC2s and acquired immune responses in the onset of allergic rhinitis induced via intranasal mucosal sensitization with antigens in mice. Naive mice were intranasally administered antigens for short-term (4 consecutive days) or long-term (21 consecutive days). The number of sneezes, serum-specific immunoglobulin E (IgE) levels, and eosinophil infiltration in the nasal mucosa were subsequently assessed. Short-term intranasal antigen administration to naive mice induced eosinophilic inflammation of the nasal mucosa in an acquired immune-independent and protease- and ILC2-dependent manner. Antigen-independent sneezing was caused by a calcium influx response via transient receptor potential vanilloid channels. By contrast, long-term intranasal mucosal sensitization with antigens led to the onset of allergic rhinitis. Furthermore, increased serum-specific IgE levels and sneezing frequency, as well as significant eosinophilic infiltration, were observed in the nasal mucosa. ILC2s in the nasal mucosa did not proliferate upon short-term stimulation with antigens but proliferated upon long-term stimulation, facilitating acquired immunity and allergic rhinitis onset. Our findings demonstrated that allergic inflammation is induced by the protease/IL-33/ILC2/IL-5 axis during the initiator phase. Acquired immunity induced by long-term sensitization and innate immunity facilitated by short-term sensitization together induce significant allergic inflammation and allergic rhinitis onset.

Group 2 innate lymphoid cells (ILC2s) contribute to the maintenance of tissue homeostasis by promoting tissue repair and regulating immune responses. However, excessive or prolonged activation of ILC2s can induce chronic inflammation and tissue fibrosis, thereby contributing to disease exacerbation and progression. Recent studies have revealed that the mechanisms underlying ILC2 activation and their effector functions vary considerably across different tissues. Therefore, understanding the tissue-specific regulation and function of ILC2s is essential for elucidating their roles in both physiological and pathological contexts. Here, we highlight the distinct functional roles of ILC2s in the stomach, intestine, lung, and skin. We examine the differences in activation cues and key effector cytokines produced by ILC2s, illustrating how these cells adapt to the unique immune environments of each tissue. Furthermore, although ILC2s were once thought to function independently of the microbiota, recent findings suggest that microbial communities may influence their activation and function. We also discuss the emerging roles of ILC2s in various diseases, including allergies, inflammatory disorders, and cancer, emphasizing their dual roles in both host defense and disease exacerbation. Gaining a deeper understanding of the distinct functional roles of ILC2s across different tissues will enhance our insight into their involvement in disease pathogenesis and may open new avenues for targeted therapeutic strategies that modulate ILC2 responses.