International immunology最新文献

Follicular helper T (Tfh) cells promote B cell differentiation and antibody production in the B cell follicles of secondary lymphoid organs. Tfh cells express their signature transcription factor BCL6, interleukin (IL)-21, and surface molecules including inducible T cell costimulator (ICOS), programmed cell death-1 (PD-1), and C-X-C motif chemokine receptor 5 (CXCR5). Migration of Tfh cells to B cell follicles largely depends on the CXCR5 expression induced by interactions with antigen-presenting dendritic cells in the T cell area. How Tfh cells acquire sufficient levels of CXCR5 expression, however, has remained unclear. Using our in vitro culture system to generate CXCR5low Tfh-like cells from naive CD4+ T cells with IL-6 in the absence of other cell types, we found that the active form of vitamin D, calcitriol, markedly enhanced CXCR5 expression after the release from persistent T cell receptor (TCR) stimulation. CH-223191, an aryl hydrocarbon receptor antagonist, further enhanced CXCR5 expression. IL-12 but not IL-4, in place of IL-6, also supported calcitriol to enhance CXCR5 expression even before the release from TCR stimulation, whereas the cell viability sharply decreased after the release. The Tfh-like cells generated with IL-6 and calcitriol exhibited chemotaxis toward C-X-C motif chemokine ligand 13 (CXCL13), expressed IL-21, and helped B cells to produce IgG antibodies in vitro more efficiently than Tfh-like cells generated without added calcitriol. Calcitriol injections into antigen-primed mice increased the proportion of CXCR5+PD-1+CD4+ cells in their lymphoid organs, and enhanced T cell entry into B cell follicles. These results suggest that calcitriol promotes CXCR5 expression in developing Tfh cells and regulates their functional differentiation.

Chronic inflammation is implicated in many types of diseases, including cardiovascular, neurodegenerative, metabolic, and immune disorders. The search for therapeutic targets to control chronic inflammation often involves narrowing down the various molecules associated with pathology that have been discovered by various omics analyses. Herein, a different approach to identify therapeutic targets against chronic inflammation is proposed and one such target is discussed as an example. In chronically inflamed tissues, a large number of cells receive diverse proinflammatory signals, the intracellular signals are intricately integrated, and complicated intercellular interactions are orchestrated. This review focuses on effectively blocking this chaotic inflammatory signaling network via the endolysosomal system, which acts as a cellular signaling hub. In endolysosomes, the inflammatory signals mediated by pathogen sensors, such as Toll-like receptors, and the signals from nutrient and metabolic pathways are integrally regulated. Disruption of endolysosome signaling results in a strong anti-inflammatory effect by disrupting various signaling pathways, including pathogen sensor-mediated signals, in multiple immune cells. The endolysosome-resident amino acid transporter, solute carrier family 15 member 4 (SLC15A4), which plays an important role in the regulation of endolysosome-mediated signals, is a promising therapeutic target for several inflammatory diseases, including autoimmune diseases. The mechanisms by which SLC15A4 regulates inflammatory responses may provide a proof of concept for the efficacy of therapeutic strategies targeting immune cell endolysosomes.

Dendritic cells (DCs) are specialized antigen-presenting cells for lymphocytes, including regulatory T (Treg) cells, a subset of CD4+ T cells expressing CD25 and Foxp3, a transcription factor. Treg cells maintain immunological self-tolerance in mice and humans, and suppress autoimmunity and other various immune responses such as tumor immunity, transplant rejection, allergy, responses to microbes, and inflammation. Treg-cell proliferation is controlled by antigen-presenting DCs. On the other hand, Treg cells suppress the function of DCs by restraining DC maturation. Therefore, the interaction between DCs and Treg cells, DC-Treg crosstalk, could contribute to controlling health and disease. We recently found that unique DC-Treg crosstalk plays a role in several conditions. First, Treg cells are expanded in ultraviolet B (UVB)-exposed skin by interacting with DCs, and the UVB-expanded Treg cells have a healing function. Second, manipulating DC-Treg crosstalk can induce effective acquired immune responses against severe acute respiratory syndrome coronavirus 2 antigens without adjuvants. Third, Treg cells with a special feature interact with DCs in the tumor microenvironment of human head and neck cancer, which may contribute to the prognosis. Understanding the underlying mechanisms of DC-Treg crosstalk may provide a novel strategy to control health and disease.

Interferons (IFNs) are cytokines produced and secreted by immune cells when viruses, tumour cells, and so forth, invade the body. Their biological effects are diverse, including antiviral, cell growth-inhibiting, and antitumour effects. The main subclasses of IFNs include type-I (e.g. IFN-α and IFN-β) and type-II (IFN-γ), which activate intracellular signals by binding to type-I and type-II IFN receptors, respectively. We have previously shown that when macrophages are treated with supersulphide donors, which have polysulphide structures in which three or more sulphur atoms are linked within the molecules, IFN-β-induced cellular responses, including signal transducer and activator of transcription 1 (STAT1) phosphorylation and inducible nitric oxide synthase (iNOS) expression, were strongly suppressed. However, the subfamily specificity of the suppression of IFN signals by supersulphides and the mechanism of this suppression are unknown. This study demonstrated that supersulphide donor N-acetyl-L-cysteine tetrasulphide (NAC-S2) can inhibit IFN signalling in macrophages stimulated not only with IFN-α/β but also with IFN-γ. Our data suggest that NAC-S2 blocks phosphorylation of Janus kinases (JAKs), thereby contributing to the inhibition of phosphorylation of STAT1. Under the current experimental conditions, the hydrogen sulphide (H2S) donor NaHS failed to inhibit IFN signalling. Similar to NAC-S2, the carbohydrate-based supersulphide donor thioglucose tetrasulphide (TGS4) was capable of strongly inhibiting tumour necrosis factor-α production, iNOS expression, and nitric oxide production from macrophages stimulated with lipopolysaccharide. Further understanding of the molecular mechanisms by which supersulphide donors exhibit their inhibitory actions towards JAK/STAT signalling is a necessary basis for the development of supersulphide-based therapeutic strategy against autoimmune disorders with dysregulated IFN signalling.

The intricate and dynamic tryptophan (Trp) metabolic pathway in both the microbiome and host cells highlights its profound implications for health and disease. This pathway involves complex interactions between host cellular and bacteria processes, producing bioactive compounds such as 5-hydroxytryptamine (5-HT) and kynurenine derivatives. Immune responses to Trp metabolites through specific receptors have been explored, highlighting the role of the aryl hydrocarbon receptor in inflammation modulation. Dysregulation of this pathway is implicated in various diseases, such as Alzheimer's and Parkinson's diseases, mood disorders, neuronal diseases, autoimmune diseases such as multiple sclerosis (MS), and cancer. In this article, we describe the impact of the 5-HT, Trp, indole, and Trp metabolites on health and disease. Furthermore, we review the impact of microbiome-derived Trp metabolites that affect immune responses and contribute to maintaining homeostasis, especially in an experimental autoimmune encephalitis model of MS.

An age-dependent increase in interferon (IFN)-γ expression by intestinal intraepithelial lymphocytes (IELs) contributes to the acquisition of resistance to infection by pathogens. However, how IELs acquire the ability to produce IFN-γ remains to be elucidated. Here, we report that IELs in the small intestine acquire the ability to rapidly produce IFN-γ at two distinct life stages. TCRαβ+ IELs (αβIELs) started producing IFN-γ at 4 weeks of age, within 1 week after weaning. In contrast, TCRγδ+ IELs (γδIELs) started producing IFN-γ at 7 weeks of age. In mice lacking Eγ4, an enhancer of the TCRγ locus (Eγ4-/- mice), Thy-1+ Vγ5+ γδIELs, a major subpopulation of γδIELs, were specifically reduced and their ability to produce IFN-γ was severely impaired, whereas Vγ2+ γδIELs normally produced IFN-γ. In Eγ4-/- mice, TCR expression levels were reduced in Vγ5+ γδIEL precursors in the thymus but unchanged in the Vγ5+ IELs. Nevertheless, TCR responsiveness in Vγ5+ γδIELs was impaired in Eγ4-/- mice, suggesting that the TCR signal received in the thymus may determine TCR responsiveness and the ability to produce IFN-γ in the gut. These results suggest that αβIELs and γδIELs start producing IFN-γ at different life stages and that the ability of Vγ5+ γδIELs to produce IFN-γ in the gut may be predetermined by TCR signalling in IEL precursors in the thymus.

The thymus is an organ required for T cell development and is also an eosinophil-rich organ; however, the nature and function of thymic eosinophils remain unclear. Here, we characterized the gene expression and differentiation mechanism of thymic eosinophils in mice. Thymic eosinophils showed a distinct gene expression profile compared with other organ-resident eosinophils. The number of thymic eosinophils was controlled by medullary thymic epithelial cells (mTECs). In Rag-deficient mice, the unique gene expression signature of thymic eosinophils was lost but restored by pre-T cell receptor signalling, which induces CD4+ CD8+ thymocyte differentiation, indicating that T cell differentiation beyond the CD4- CD8- stage is necessary and sufficient for the induction of thymic eosinophils. These results demonstrate that thymic eosinophils are quantitatively and qualitatively regulated by mTECs and developing thymocytes, respectively, suggesting that thymic eosinophils are a distinct, thymus-specific cell subset, induced by interactions with thymic cells.

The generation and maintenance of memory T cells are regulated by various factors, including cytokines. Previous studies have shown that IL-27 is produced during the early acute phase of Plasmodium chabaudi chabaudi AS (Pcc) infection and inhibits the development of Th1-type memory CD4+ T cells. However, whether IL-27 acts directly on its receptor on Plasmodium-specific CD4+ T cells or indirectly via its receptor on other immune cells remains unclear. We aimed to determine the role of IL-27 receptor signaling in different immune cell types in regulating the generation and phenotype of memory CD4+ T cells during Plasmodium infection. We utilized Plasmodium-specific T-cell antigen receptor (TCR) transgenic mice, PbT-II, and Il27rα-/- mice to assess the direct and indirect effects of IL-27 signaling on memory CD4+ T-cell generation. Mice were transferred with PbT-II or Il27rα-/- PbT-II cells and infected with Pcc. Conditional knockout mice lacking the IL-27 receptor in T cells or dendritic cells were employed to discern the specific immune cell types involved in IL-27 receptor signaling. High levels of memory in PbT-II cells with Th1-shift occurred only when both PbT-II and host cells lacked the IL-27 receptor, suggesting the predominant inhibitory role of IL-27 signaling in both cell types. Furthermore, IL-27 receptor signaling in T cells limited the number of memory CD4+ T cells, while signaling in both T and dendritic cells contributed to the Th1 dominance of memory CD4+ T cells. These findings underscore the complex cytokine signaling network regulating memory CD4+ T cells during Plasmodium infection.

Allergy is a complex array of diseases influenced by innate and adaptive immunity, genetic polymorphisms, and environmental triggers. Atopic dermatitis is a chronic inflammatory skin disease characterized by barrier defects and immune dysregulation, sometimes leading to asthma and food allergies because of the atopic march. During atopic skin inflammation, Langerhans cells and dendritic cells (DCs) in the skin capture and deliver allergen information to local lymph nodes. DCs are essential immune sensors coordinating immune reactions by capturing and presenting antigens to T cells. In the context of allergic responses, DCs play a crucial role in instructing two types of helper T cells-type 2 helper T (Th2) cells and follicular helper T (TFH) cells-in allergic responses and IgE antibody responses. In skin sensitization, the differentiation and function of Th2 cells and TFH cells are influenced by skin-derived factors, including epithelial cytokines, chemokines, and signalling pathways to modify the function of migratory DCs and conventional DCs. In this review, we aim to understand the specific mechanisms involving DCs in allergic responses to provide insights into the pathogenesis of allergic diseases and potential therapeutic strategies.

Atopic dermatitis (AD), a prevalent Th2-dominant skin disease, involves complex genetic and environmental factors, including mutations in the Filaggrin gene and dysbiosis of skin microbiota characterized by an increased abundance of Staphylococcus aureus. Our recent findings emphasize the pivotal role of the skin barrier's integrity and microbial composition in infantile AD and allergic diseases. Early skin dysbiosis predisposes infants to AD, suggesting targeted skincare practices as a preventive strategy. The effects of skincare interventions, particularly the application of moisturizers with the appropriate molar concentration of ceramides, cholesterol, and fatty acids, play a crucial role in restoring the skin barrier. Notably, our study revealed that appropriate skincare can reduce Streptococcus abundance while supporting Cutibacterium acnes presence, thus directly linking skincare practices to microbial modulation in neonatal skin. Despite the mixed outcomes of previous Randomized Controlled Trials on the efficacy of moisturizers in AD prevention, our research points to the potential of skincare intervention as a primary preventive method against AD by minimizing the impact of genetic and environmental factors. Furthermore, our research supports the notion that early aggressive management of eczema may reduce the incidence of food allergies, highlighting the necessity for multifaceted prevention strategies that address both the skin barrier and immune sensitization. By focusing on repairing the skin barrier and adjusting the skin's microbiome from birth, we propose a novel perspective on preventing infantile AD and allergic diseases, opening new avenues for future studies, and practices in allergy prevention.