International immunology最新文献

{"title":"Toll-like receptors 7 and 8 as therapeutic targets for human diseases.","authors":"Ryutaro Fukui, Kensuke Miyake","doi":"10.1093/intimm/dxag052","DOIUrl":"https://doi.org/10.1093/intimm/dxag052","url":null,"abstract":"<p><p>Toll-like receptor 7 (TLR7) and TLR8 respond to pathogen-derived single-stranded RNA (ssRNA), orchestrating innate immune defense responses upon infections. However, aberrant recognition of endogenous ssRNAs by these sensors can cause various pathologies, including systemic lupus erythematosus (SLE), familial histiocytosis, immunodeficiency, and bone marrow failure. Recent insights into genetic variations in TLR7/8 and functionally associated genes have elucidated the mechanisms that prevent excessive TLR7/8 activation. Specifically, TLR7/8 responses are negatively regulated by several mechanisms, including the TLR-specific chaperone UNC93B1, lysosomal NADPH oxidase NOX2, the lysosomal nuclease PLD4, and the lysosomal nucleoside transporter SLC29A3. Given the link between dysregulated TLR7/8 activation and diseases development, therapeutic agents targeting these receptors are currently under clinical trials to evaluate their efficacy in treating SLE.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thymic cortical epithelial Psmb11-encoded β5t in mouse and human.","authors":"Mei-Ting Yang, Akihide Shimizu, Mami Matsuda-Lennikov, Jie Li, Meleca Gluckman, Alison Jacques, Shigeo Murata, Rhonda R Roberts, Tessa W Caceres, Sandra S Garcia-Buntley, Simona Colantonio, Yousuke Takahama","doi":"10.1093/intimm/dxag031","DOIUrl":"10.1093/intimm/dxag031","url":null,"abstract":"<p><p>Psmb11-encoded β5t is a proteolytic subunit of thymoproteasomes expressed in cortical thymic epithelial cells (cTECs). β5t-containing thymoproteasomes are essential for the thymic generation of CD8-lineage cytotoxic T cells. Here, we outline the current understanding of the mechanisms underlying thymoproteasome-dependent CD8 T cell development. We focus on the cTEC-specific expression of β5t, highlighting its unique expression in comparison with the transcription factor Foxn1, which is expressed in both thymic and skin epithelial cells. Additionally, we discuss our recent engineering of monoclonal antibodies that are specific for mouse and human β5t. β5t not only provides an important machinery for CD8 T cell development but also serves as a valuable tool for further study of the biology of thymic epithelial cells in health and disease.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"594-602"},"PeriodicalIF":3.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13281738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial transfer-driven immune evasion in the tumor microenvironment.","authors":"Li Zhu, Yosuke Togashi","doi":"10.1093/intimm/dxag027","DOIUrl":"10.1093/intimm/dxag027","url":null,"abstract":"<p><p>The tumor microenvironment (TME) is a complex landscape where metabolic interactions significantly dictate antitumor immunity. Immune evasion in cancer is typically discussed in terms of inhibitory receptors and ligands, suppressive cytokines, defective antigen presentation, and metabolic competition. However, recent evidence reveals that intercellular mitochondrial transfer adds a new mechanism of immune evasion in the TME. The mitochondrial fitness of T cells is central to sustained effector function, memory formation, and responsiveness to immune-checkpoint blockade. Tumor cells can act as pathogenic mitochondrial donors, transferring functional or dysfunctional mitochondria to neighboring T cells via tunneling nanotubes and extracellular vesicles. This process involves a mitophagy imbalance that leads to the homoplasmic replacement of endogenous mitochondria, thereby driving T-cell senescence, impairing memory formation and long-term antitumor function, and ultimately weakening cancer immunosurveillance. Overall, mitochondrial transfer should be considered a new part of the tumor immune evasion framework. It also provides new therapeutic opportunities for improving cancer immunotherapy.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"603-609"},"PeriodicalIF":3.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alarmin cues and regulated cell death calibrate mucosal immunoglobulin A responses and virologic control after intranasal whole-virion inactivated influenza vaccination.","authors":"Eita Sasaki, Hideki Asanuma, Yoshimasa Takahashi, Hideki Hasegawa","doi":"10.1093/intimm/dxag023","DOIUrl":"10.1093/intimm/dxag023","url":null,"abstract":"<p><p>How tissue damage cues and regulated cell death programs instruct antigen-specific mucosal immunoglobulin A (IgA) after vaccination remains incompletely defined. Using a mouse model of intranasal whole-virion inactivated influenza vaccination, we identify two proximal inputs that shape antibody output and virologic control: epithelial necroptosis-associated interleukin (IL)-33 release and a macrophage death-program switch that unmasks IL-1α. Immunization was accompanied by lung cell death, IL-33 release, and the induction of antigen-specific mucosal IgA. In alveolar macrophages, vaccine uptake required phagocytosis and was associated with lysosomal destabilization and cathepsin B activity, which were linked to IL-1α release under conditions that favored regulated necrotic cell death. Consistent with this, pharmacologic inhibition of caspases shifted the dominant death program in alveolar macrophages and was associated with enhanced B cell activation in the cervical lymph nodes and increased iIgA-producing cell-like populations. At the functional level, caspase inhibition augmented vaccine-elicited protection, including reduced lung viral titers and attenuated pathology after homologous challenge and improved control of a within-subtype drift influenza A virus challenge strain; these enhancements were partly dependent on IL-1α. Together, these data support a model in which alarmin cues and regulated cell death pathways in the lung modulate the magnitude of mucosal IgA responses and contribute to virologic control after intranasal whole-virion inactivated influenza vaccination. Limitations include reliance on pharmacologic pathway modulation and a mouse intranasal whole-virion inactivated influenza vaccine model; thus, mechanistic generalization beyond this context should be made cautiously.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"626-644"},"PeriodicalIF":3.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147929107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Granulocyte heterogeneity in immune-mediated and inflammatory diseases: insights from single-cell transcriptomic analyses.","authors":"Hiroshi Shimagami, Atsushi Kumanogoh, Masayuki Nishide","doi":"10.1093/intimm/dxag026","DOIUrl":"10.1093/intimm/dxag026","url":null,"abstract":"<p><p>Neutrophils and eosinophils have long been regarded as terminal effectors of innate immunity. Technical advances in single-cell RNA sequencing define transcriptome-based granulocyte subsets beyond classical density- and surface marker-based classifications. These approaches reveal substantial heterogeneity in granulocyte differentiation states, activation programs, and tissue adaptation across human diseases. In microscopic polyangiitis, type II interferon (IFN) pathways shape a pathogenic neutrophil activation state, and serum IFNγ levels at disease onset may serve as a potential biomarker for subsequent relapse. In infectious diseases, including coronavirus disease 2019 (COVID-19) and sepsis, the expansion of immunosuppressive ARG1- and IL1R2-expressing neutrophils is reported in severe disease and may reflect altered immune responses. MMP9-high neutrophils are enriched in cardiovascular disorders and may be linked to thrombosis and ischemic injury. In allergic diseases, spatial and single-cell analyses identify tissue-specific eosinophil states and their interactions with epithelial and macrophage compartments, highlighting context-dependent eosinophil activation within inflamed tissues. Despite emerging evidence for disease-associated granulocyte heterogeneity, whether these populations causally contribute to disease pathophysiology remains largely unclear. Experimentally validated functions and clinically applicable surrogate markers, such as surface markers or circulating proteins, are still needed. This review summarizes recent advances and current limitations in understanding granulocyte heterogeneity across immune-mediated and inflammatory diseases and discusses how integrative single-cell approaches may support the development of clinically relevant biomarkers and targeted therapeutic strategies.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"585-593"},"PeriodicalIF":3.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148015364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interleukin-10/interleukin-10Rα axis in fibroblasts limits large intestinal pathology by suppressing Type I interferon signaling.","authors":"Takayoshi Ito, Bo Li, Taiki Sakaguchi, Mayu Yagita-Sakamaki, Hiroyuki Itoi, Mari Murakami, Runlin Wu, Akio Fukada, Daisuke Motooka, Takayuki Ogino, Shota Nakamura, Daisuke Okuzaki, Kiyoshi Takeda, Hisako Kayama","doi":"10.1093/intimm/dxag022","DOIUrl":"10.1093/intimm/dxag022","url":null,"abstract":"<p><p>Recent studies identified that the dysregulation of fibroblast activity, in addition to impairment in epithelial integrity and uncontrolled immune response, is implicated in the pathogenesis of inflammatory bowel disease (IBD). The anti-inflammatory cytokine interleukin (IL)-10 and its receptors IL-10Rα and IL-10Rβ have IBD-associated single nucleotide polymorphisms. In the intestine, IL-10 signaling is essential for maintaining an anti-inflammatory state of myeloid cells and inducing regulatory T cells, thereby preventing intestinal inflammation linked to IBD development. However, its impact on the physiology and pathophysiology of intestinal fibroblasts is poorly understood. Here, we show that Il10ra deficiency leads to increased expression of a subset of genes in colonic fibroblasts, most of which are associated with the Type I interferon (IFN) and Type II IFN signaling pathways. In addition, Pdgfra-cre; Il10raf/f mice aged 16 weeks or older develop chronic spontaneous colitis and subsequent fibrosis accompanied by enhanced infiltration by myeloid cells and effector CD4+ T cells in the lamina propria of the colon. Moreover, Pdgfra-cre; Il10raf/f mice at 12 weeks of age exhibit more severe clinical symptoms than those of Il10raf/f mice during dextran sodium sulfate-induced colitis that can be suppressed by the administration of anti-IFNAR1 antibody but not anti-IFNGR1 antibody. Therefore, inhibition of the Type I IFN pathway via IL-10Rα signaling in fibroblasts is one of the IL-10-dependent mechanisms underlying the prevention of large intestinal pathology.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"610-625"},"PeriodicalIF":3.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147929110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory T cells exhibit differential therapeutic effects across tissues during chronic autoimmune inflammation.","authors":"Yuji Nishimura, Yosuke Nagahata, Daiya Ohara, Koji Terada, Yuka Kobayashi, Yasutoshi Agata, Keiji Hirota, Hiroshi Kawamoto","doi":"10.1093/intimm/dxag051","DOIUrl":"https://doi.org/10.1093/intimm/dxag051","url":null,"abstract":"<p><p>Current therapies for autoimmune diseases rely largely on non-specific immunosuppression, which can lead to adverse effects such as malignancy and severe infections. Treg-based therapies have therefore attracted attention as a more targeted approach, particularly in preventive or early-stage settings. However, their efficacy after disease onset, especially in chronic inflammation, remains poorly established. Furthermore, it remains unclear whether Treg therapy exerts uniform therapeutic effects across tissues within the same individual. Here, we demonstrate that Tregs retain therapeutic potential in chronic autoimmune inflammation, but their efficacy differs between tissues. Using a TCR-retrogenic mouse model, in which monoclonal autoreactive CD4+ T cells drive spontaneous chronic dermatitis and arthritis, polyclonal Treg administration effectively resolved chronic dermatitis but only limited disease progression in chronic arthritis. Despite these differences in outcomes, transferred Tregs were detected in local tissues and draining lymph nodes, suggesting that tissue-specific environments may underlie differential therapeutic responsiveness. To investigate the basis of this difference, we performed microarray and GSVA-based pathway analyses. Under untreated conditions, skin and joint tissues exhibited distinct baseline pathway activity patterns, with the skin showing higher activity of the Hippo signaling pathway, a growth-regulatory pathway, and the joints displaying stronger enrichment of inflammation-related pathways, including complement- and angiogenesis-associated pathways. Following Treg administration, skin-but not joint-tissue showed pathway modulation, including increased Wnt and decreased IL-17 signaling pathway activity, consistent with a more reparative environment. These findings indicate that distinct inflammatory environments underlie differential responsiveness to Treg therapy across tissues, highlighting their context-dependent therapeutic potential in chronic autoimmune inflammation.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTPN22 mediates delayed negative feedback of T cell activation by forming an inhibitory signaling complex.","authors":"Akiko Hashimoto-Tane, Yusuke Kawashima, Machie Sakuma, Natsumi Yoneda, Natsuko Tanimura, Manabu Nakayama, Haruhiko Koseki, Osamu Ohara, Bernard Malissen, Takashi Saito","doi":"10.1093/intimm/dxag050","DOIUrl":"https://doi.org/10.1093/intimm/dxag050","url":null,"abstract":"<p><p>PTPN22 is a cytosolic tyrosine phosphatase expressed in immune cells that negatively regulates T cell receptor (TCR) signaling and implicated in autoimmune diseases through a common (R620W) variant. The molecular mechanisms by which PTPN22 modulates TCR activation remain incompletely understood. Here we show that upon T cell activation, PTPN22 forms delayed clusters at TCR microclusters (MCs) alongside Csk, STS-1 and PSTPIP, constituting a feedback inhibitory complex. Using imaging analyses, MS, and knockout mouse models, we demonstrate that this complex functions as a delayed negative regulation of TCR signaling, and that autoimmune-associated PTPN22 (R620W) mutant exhibits reduced binding to Csk and STS-1, impairing complex formation. Consequently, T cells expressing the mutant display enhanced cytokine production and immune responses. These findings reveal cooperative inhibitory mechanism involving PTPN22 and its partners that modulates T cell activation, providing insights into how PTPN22 variants contribute to autoimmune disease susceptibility.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polymorphic tail of HLA-DQ leads to the heterogeneous IL-10 response of antigen-presenting cells.","authors":"Sho Matsushita, Rie Takagi, Mieko Tokano, Kazuyuki Nakagome, Tomoyuki Soma, Makoto Nagata, Masaaki Kawano","doi":"10.1093/intimm/dxag049","DOIUrl":"https://doi.org/10.1093/intimm/dxag049","url":null,"abstract":"<p><p>The cytoplasmic tails of HLA molecules are heterogeneous and polymorphic in terms of length and amino-acid sequences. We previously showed that class II HLA molecules transmitted signals in antigen presentation, and cross-linking HLA-DQ induced the interleukin (IL)-10 response of monocytes via p38MAPK. In this study, cross-linking DQ of B cells led to the phosphorylation of Ser-255 of Hsp90β. Hsp90 and casein kinase (CK) 2 which can catalyze this phosphorylation pattern, were co-immunoprecipitated with DQ. The long-form DQ tail-derived peptides bound to CK2 protein with higher affinity. The crosslinking-induced IL-10 response was suppressed by specific inhibition of Hsp90 and CK2. Furthermore, anti-Hsp90 antibody co-immunoprecipitated mitogen-activated protein kinase kinase kinase 3 (MEKK3) and cerebral cavernous malformations 2 (CCM2), a scaffold for p38MAPK activation. Cross-linking DQ augmented co-immunoprecipitation of MEKK3 with CCM2, in an Hsp90-dependent manner. HLA-DQ thereby qualitatively controls heterogeneous immune responses through its polymorphic tails via HLA-kinase-chaperone-scaffold-MAPK cascade signaling into antigen-presenting cells. Subjects with long-form DQ alleles showed elevated plasma IL-10 and IgG4 levels. These observations shed light on the novel non-classical function of HLA molecules.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STK11 deficiency drives NSCLC immune resistance via ETNK2-mediated phosphoethanolamine accumulation.","authors":"Wei Zhang, Jing Hu, Zhengbin Zhang","doi":"10.1093/intimm/dxag048","DOIUrl":"https://doi.org/10.1093/intimm/dxag048","url":null,"abstract":"<p><p>STK11/LKB1 mutations are critical drivers of primary resistance to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC); however, the metabolic mechanisms by which STK11 deficiency remodels the tumor microenvironment (TME) to induce an immunosuppressive state remain largely elusive. By performing metabolomics and liquid chromatography-mass spectrometry (LC-MS) analysis on tumor interstitial fluid (TIF) from STK11-deficient patient-derived xenograft (PDX) and syngeneic mouse CMT167 models, we investigated the metabolic landscape and its impact on CD8+ T cell functionality. We further integrated biochemical assays (ChIP, Co-IP, and dual-luciferase) and engineered small extracellular vesicles (sEVs) to dissect the upstream regulatory network and evaluate therapeutic potential. We identified a significant and specific accumulation of phosphoethanolamine (pEtn) in the STK11-deficient TIF, which directly impairs CD8+ T cell effector functions by downregulating membrane diacylglycerol (DAG) and blocking proximal T cell receptor (TCR) signaling. Mechanistically, STK11 loss triggers mitochondrial reactive oxygen species (ROS) accumulation, which inhibits prolyl hydroxylases (PHDs) and prevents the VHL-mediated degradation of HIF1A. Stabilized HIF1A subsequently recruits the demethylase TET1 to the ETNK2 promoter, driving its epigenetic activation and excessive pEtn synthesis. Clinical analyses confirm that high ETNK2 expression correlates with poor ICI response and shortened survival. Targeted delivery of siETNK2 via EGFR-targeted exosomes effectively lowered TIF pEtn concentrations, restored T cell activity, and sensitized STK11-deficient tumors to PD-1 blockade in vivo. This study elucidates a novel \"mitochondrial ROS-HIF1A-TET1-ETNK2\" metabolic-epigenetic axis, providing a precise interventional strategy to overcome genotype-specific immune resistance in NSCLC.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}