International Immunology[JOURNAL]
Sun
200 papers
Thymic cortical epithelial Psmb11-encoded β5t in mouse and human.
Yang MT, Shimizu A, Matsuda-Lennikov M … +9 more , Li J, Gluckman M, Jacques A, Murata S, Roberts RR, Caceres TW, Garcia-Buntley SS, Colantonio S, Takahama Y
Int Immunol · 2026 Jun · PMID 42261593 · Full text
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 ce...
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.
Signaling and Transcriptional Control of Thymocyte Differentiation.
Taniuchi I
Int Immunol · 2026 Jun · PMID 42237593 · Publisher ↗
This review summarizes key topics discussed in the session "Biology within the Thymus" at the 54th Annual Meeting of the Japanese Society for Immunology, which highlighted recent advances in our understanding of T-cell d...
This review summarizes key topics discussed in the session "Biology within the Thymus" at the 54th Annual Meeting of the Japanese Society for Immunology, which highlighted recent advances in our understanding of T-cell development and fate determination. In particular, the session focused on transcriptional regulation of T-lineage commitment and the mechanisms by which T-cell receptor (SP) signaling governs thymocyte differentiation. Early T-lineage commitment is established through the integration of thymic microenvironmental cues and intrinsic transcription factors, including Bcl11b, PU.1, and Runx family proteins. Among these, Runx transcription factors play essential roles throughout thymocyte development, not primarily through changes in expression but through dynamic regulation of their molecular interactions and genomic occupancy. Following commitment, αβTCR-expressing CD4+CD8+ double-positive (DP) thymocytes undergo MHC-dependent selection and differentiate into CD4+ helper or CD8+ cytotoxic T cells. Although the core components of proximal TCR signaling are largely shared, accumulating observations suggest that qualitative and quantitative differences in signaling-shaped by signal strength, duration, and subcellular context-may contribute to lineage specification. In this regard, recent studies discussed in this session highlighted the role of co-receptor-free Lck as an active signaling pool capable of initiating TCR signaling independently of CD4 or CD8 association, thereby adding an additional layer of complexity to MHC-dependent thymic selection. In addition, post-translational modification of Runx proteins, particularly within the conserved WRPY motif, has emerged as a molecular link between proximal TCR signaling mediated by kinases such as Lck and lineage-specific transcriptional repression. Together with advances in thymic culture systems, genome editing, and proteomic approaches, these findings underscore the tight coupling between proximal TCR signaling-including both co-receptor-dependent and co-receptor-independent Lck activity-and transcriptional regulation, and highlight Runx transcription factors as key integrators that translate MHC-specific TCR signals into transcriptional programs determining thymocyte fate.
17,18-epoxyeicosatetraenoic acid and its metabolite attenuate IL-33-induced airway inflammation involving group 2 innate lymphoid cells.
Tojima I, Nishiguchi T, Kawakita K … +8 more , Kubo Y, Murao T, Nakamura K, Matsumoto K, Kouzaki H, Shimizu S, Shimizu T, Takenaka Y
Int Immunol · 2026 Jun · PMID 42231621 · Publisher ↗
Group 2 innate lymphoid cells (ILC2s) play critical roles in type 2 airway inflammation. 17,18-epoxyeicosatetraenoic acid (17,18-EpETE), an eicosapentaenoic acid metabolite, is generated from dietary omega-3 fatty acids,...
Group 2 innate lymphoid cells (ILC2s) play critical roles in type 2 airway inflammation. 17,18-epoxyeicosatetraenoic acid (17,18-EpETE), an eicosapentaenoic acid metabolite, is generated from dietary omega-3 fatty acids, and may have anti-inflammatory activities. We evaluated the effect of 17,18-EpETE and its metabolite, 17,18-dihydroxy-eicosa-5,8,11,14-tetraenoic acid (17,18-diHETE), on IL-33-induced airway inflammation involving ILC2s. We evaluated the in vitro effects of 17,18-EpETE and 17,18-diHETE on the IL-33-induced production of IL-5 and IL-13 by human ILC2s (isolated from peripheral blood) using ELISA. Expression of the corresponding fatty acid receptors and the GATA-3 transcription factor were examined using flow cytometry and quantitative RT-PCR. Additionally, we examined the in vivo effects of 17,18-EpETE or 17,18-diHETE in a mouse model of type 2 airway inflammation induced by intranasal (i.n.) instillation of IL-33. 17,18-EpETE or 17,18-diHETE inhibited IL-33-induced production of IL-5 and IL-13, and IL-33-induced expression of GATA-3 in human ILC2s. GW1100, an antagonist of G protein-coupled receptor (GPR) 40, or GW9662, an antagonist of peroxisome proliferator-activated receptor γ (PPARγ), counteracted the inhibitory effects of 17,18-EpETE or 17,18-diHETE on the IL-33-induced production of IL-5 and IL-13 by ILC2s. I.n. administration of 17,18-EpETE or 17,18-diHETE attenuated IL-33-induced eosinophil infiltration and mucus production in mouse nasal mucosa, and production of IL-5 and IL-13 in lung tissue and bronchoalveolar lavage fluid. The present study demonstrated the anti-inflammatory effects of 17,18-EpETE and 17,18-diHETE on IL-33-induced airway inflammation involving ILC2s. I.n. administration of 17,18-EpETE may be a new therapeutic approach for the treatment of intractable type 2 airway inflammation.
FcμR enhances recall responses by promoting the generation of CD80+PD-L2+ memory B cells.
Zhang R, Sun J, Dong L … +19 more , Hu Z, Min Q, Wang Y, Wen Z, Zhao J, Wang J, Liu J, Feng X, Luan Y, Meng X, Yu M, Li Y, Cui C, Lu C, Wu X, Hase K, Takahashi Y, Kurosaki T, Wang JY
Int Immunol · 2026 Jun · PMID 42226640 · Publisher ↗
The IgM Fc receptor (FcμR), the sole receptor specific for IgM, is crucial for B cell survival and humoral immunity. Yet, its role in memory B cells (MBCs) has remained unclear. Here, we show that FcμR-/- mice immunized...
The IgM Fc receptor (FcμR), the sole receptor specific for IgM, is crucial for B cell survival and humoral immunity. Yet, its role in memory B cells (MBCs) has remained unclear. Here, we show that FcμR-/- mice immunized with the T-dependent antigen 4-hydroxy-3-nitrophenyl acetyl-chicken γ-globulin (NP-CGG) generate normal numbers of IgG1+ MBCs with long-term survival comparable to that of WT mice. However, the IgG1+ MBCs in FcμR-/- mice contained a reduced proportion of mature CD80+PD-L2+ cells, a subset associated with potent recall responses and plasma cell differentiation. Consistently, adoptive transfer of NP-specific MBCs and CGG-specific memory T cells into Rag1-/- mice revealed significantly diminished memory B cell responses in recipients of FcμR-/- MBCs. Mechanistically, FcμR-/- IgG1+ MBCs exhibited impaired B cell receptor signaling and reduced activation of transcription factors essential for plasma cell differentiation upon antigen re-challenge both in vivo and in vitro. Together, these findings establish FcμR as a previously unrecognized key regulator of CD80+PD-L2+ MBC formation and recall responses.
Mitochondrial Transfer-Driven Immune Evasion in the Tumor Microenvironment.
Zhu L, Togashi Y
Int Immunol · 2026 May · PMID 42212533 · Publisher ↗
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,...
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.
Granulocyte heterogeneity in immune-mediated and inflammatory diseases: Insights from single-cell transcriptomic analyses.
Shimagami H, Kumanogoh A, Nishide M
Int Immunol · 2026 May · PMID 42186818 · Publisher ↗
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...
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 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 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.
Beyond B cell helpers: diverse roles of peripheral helper T cells.
Masuo Y, Yoshitomi H
Int Immunol · 2026 May · PMID 42136142 · Publisher ↗
Peripheral helper T cells (TPH cells) constitute a subset of CD4+ T cells that provide help to B cells in inflamed non-lymphoid tissues. TPH cells have been identified across various chronic disorders, especially autoimm...
Peripheral helper T cells (TPH cells) constitute a subset of CD4+ T cells that provide help to B cells in inflamed non-lymphoid tissues. TPH cells have been identified across various chronic disorders, especially autoimmune diseases, and accumulating evidence suggests their involvement in disease pathogenesis. However, the mechanisms by which TPH cells drive persistent inflammation remain incompletely understood. Recent insights reveal that TPH cells play additional roles in local immune responses beyond their classical B cell helper function. In this review, we explore the heterogeneity and functional diversity of TPH cells that contribute to chronic inflammatory processes within target tissues of autoimmunity. These functions of TPH cells include their stem-like capacity to serve as a reservoir and replenish activated cells in situ as well as their direct role in the activation of macrophages through proinflammatory soluble factors. We further discuss the dynamic interplay between TPH cells and tertiary lymphoid structures (TLSs), highlighting the chemokine regulation for TLS formation and the essential niche these structures offer for the TPH cell maturation. A deeper understanding of TPH cell-mediated tissue inflammation will pave the way for the development of novel therapeutic strategies in persistent autoimmune conditions.
The intestine as a nexus of tissue-encoded immunological memory.
Murakami M, Takeda K
Int Immunol · 2026 May · PMID 42130264 · Publisher ↗
The intestine is continuously exposed to diverse microbial, dietary, and environmental signals, requiring tightly regulated immune responses that balance host defense and tolerance. Recent advances in single-cell and mul...
The intestine is continuously exposed to diverse microbial, dietary, and environmental signals, requiring tightly regulated immune responses that balance host defense and tolerance. Recent advances in single-cell and multiomic technologies have revealed that immune regulation in barrier tissues cannot be fully explained by circulating immune cells but also by coordinated interactions within local tissue microenvironments. In this review, we introduce a conceptual framework that positions the intestine as a hub of tissue-encoded immune programming. Immune states are established through multilayered systems comprising cellular memory, niche memory, and multicellular circuit stabilization across immune, epithelial, and stromal compartments. These programs are reinforced by epigenetic remodeling, transcription factor networks, and metabolic-epigenetic coupling, enabling long-term adaptation to environmental cues. Within the intestinal microenvironment, specialized antigen-sampling pathways and epithelial barrier programs, together with microbiota-derived cues, actively instruct the localization, differentiation, and functional tuning of tissue-adapted immune populations, including tissue-resident memory T cells (TRM). Importantly, these locally imprinted programs can disseminate systemically and influence immune responses in distal tissues. In inflammatory bowel disease (IBD), these tissue-encoded immune programs become pathologically stabilized, enabling TRM and multicellular circuits to sustain chronic inflammation even in the absence of ongoing triggering signals. This perspective highlights tissue-encoded immune states as central regulators of immunity and disease.
Alarmin cues and regulated cell death calibrate mucosal immunoglobulin A responses and virologic control after intranasal whole-virion inactivated influenza vaccination.
Sasaki E, Asanuma H, Takahashi Y … +1 more , Hasegawa H
Int Immunol · 2026 May · PMID 42128806 · Publisher ↗
How tissue damage cues and regulated cell death programs instruct antigen-specific mucosal IgA after vaccination remains incompletely defined. Using a mouse model of intranasal whole-virion inactivated influenza vaccinat...
How tissue damage cues and regulated cell death programs instruct antigen-specific mucosal 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-33 release and a macrophage death-program switch that unmasks interleukin-1α. Immunization was accompanied by lung cell death, interleukin-33 release, and the induction of antigen-specific mucosal immunoglobulin A. In alveolar macrophages, vaccine uptake required phagocytosis and was associated with lysosomal destabilization and cathepsin B activity, which were linked to interleukin-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 immunoglobulin A-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 interleukin-1α. Together, these data support a model in which alarmin cues and regulated cell death pathways in the lung modulate the magnitude of mucosal immunoglobulin A 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.
The IL-10/IL-10Rα axis in fibroblasts limits large intestinal pathology by suppressing type I interferon signaling.
Ito T, Li B, Sakaguchi T … +11 more , Yagita-Sakamaki M, Itoi H, Murakami M, Wu R, Fukada A, Motooka D, Ogino T, Nakamura S, Okuzaki D, Takeda K, Kayama H
Int Immunol · 2026 May · PMID 42120015 · Publisher ↗
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...
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 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 of 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 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.
Selective decreases in regulatory B cell (Breg) subsets in active uveitis: IL-10+CD19+CD24hiCD38hiBreg in patients and B10 Breg in mice.
Chen YH, Zhang X, Eskandarpour M … +3 more , Gilbert RM, Lightman S, Calder VL
Int Immunol · 2026 May · PMID 42093628 · Publisher ↗
Several regulatory B lymphocyte (Breg) subsets have been implicated in autoimmune diseases. We investigated Breg subsets in non-infectious uveitis (NIU) and in mouse models of experimental autoimmune uveitis (EAU). Blood...
Several regulatory B lymphocyte (Breg) subsets have been implicated in autoimmune diseases. We investigated Breg subsets in non-infectious uveitis (NIU) and in mouse models of experimental autoimmune uveitis (EAU). Bloods from NIU patients with active disease (n=13), in remission (n=37) and healthy controls (n=10) were immunophenotyped for CD19+CD24hiCD38lo, CD19+CD24hiCD38hi immature (iBreg) and CD19+CD38intCD24int-mature Breg. In NIU, levels of peripheral blood iBreg and serum IL-10 were decreased in active disease vs. remission (P<0.01). In quiescent NIU, iBreg were isolated and, when added at increasing ratios to autologous CD3+T cells, downregulated T cell proliferation. In an EAU model, at peak disease, CD19+CD1dhiCD5+-B10, CD19+CD5+-B1, transitional 2 marginal-zone precursor CD19+CD21hiCD24hiCD23+-T2-MZP and marginal-zone B CD19+CD21hiCD23--MZB Breg subsets were analyzed both phenotypically and functionally. In EAU spleens, all Breg subsets investigated were detectable, but the IL-10-expressing B10 Breg subset was immunosuppressive and inversely correlated with disease severity (P = 0.048, R2 = 0.47). Blood-derived IL-10-expressing B10 and B1 Breg cells were increased in both adjuvant controls and EAU but were significantly reduced in clinically milder EAU. In dissociated retinal cells, only the B10 Breg subset was detectable and increased in EAU. Selective Breg subsets may be immunosuppressive, with iBreg in NIU and IL-10-expressing B10 Bregs in EAU.
Distinct fibrosis-associated macrophage subsets coordinate iron metabolism in pulmonary fibrosis.
Nabeshima H, Fukushima K, Liu YC … +20 more , Motooka D, Niitsu T, Fukui E, Ichii M, Nii T, Akamine Y, Hamada N, Hashimoto K, Abe Y, Nagahama Y, Matsuki T, Tsujino K, Miki K, Wing JB, Hosen N, Shintani Y, Kumanogoh A, Okuzaki D, Kida H, Akira S
Int Immunol · 2026 Apr · PMID 42028853 · Publisher ↗
Pulmonary fibrosis has a poor prognosis due to challenges in early diagnosis and therapeutic intervention. Current treatments remain largely ineffective due to an incomplete understanding of the complex pathology, includ...
Pulmonary fibrosis has a poor prognosis due to challenges in early diagnosis and therapeutic intervention. Current treatments remain largely ineffective due to an incomplete understanding of the complex pathology, including the interactions between fibroblasts and profibrotic immune cells within fibrotic lungs. To elucidate the dynamics of fibrosis, we performed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid (BALF) obtained from patients with interstitial lung disease (ILD). We identified the SPP1- and APOE-expressing macrophage population that is commonly present across ILDs. Histological analysis showed that this macrophage population accumulated at the center of fibrotic foci. Furthermore, the ratio of this macrophage population was increased in both progressive pulmonary fibrosis (PPF) and idiopathic pulmonary fibrosis (IPF). Transcriptomic analysis further divided this macrophage population into two subsets: SLC40A1+ or HAMP+ fibrosis-associated macrophages. We found that the relative balance of IL-10 and IL-8 regulated SLC40A1 and HAMP expression within fibrosis-associated macrophages. Additionally, histological analysis revealed that bronchial epithelium expressed IL-8, while type II alveolar epithelial cells expressed IL-10 in the fibrotic lung. SLC40A1+ fibrosis-associated macrophages localized to CD31+ perivascular regions and mediated the uptake and degradation of the hemoglobin-haptoglobin complex. This dual pathway-providing iron via SLC40A1 and intracellular iron accumulation via HAMP-facilitated the transition of fibroblasts into SPP1+ myofibroblasts. Moreover, ferroptotic fibroblasts secreted TGF-β1, which further contributes to fibrotic progression. In conclusion, aberrant iron metabolism orchestrated by fibrosis-associated macrophages may contribute to fibrosis by facilitating the transition of myofibroblasts. These findings provide mechanistic insight into the progression of autonomous pulmonary fibrosis.
PDLIM4 promotes dephosphorylation of STAT transcription factors by recruiting PTP-BL and inhibits Th1, Th2, and Th17 cell differentiation.
Jodo A, Nakahira M, Kochi Y … +3 more , Sugimoto-Ishige A, Kaisho T, Tanaka T
Int Immunol · 2026 Apr · PMID 42028851 · Publisher ↗
STAT transcription factors are activated by tyrosine phosphorylation after cytokine stimulation and are critical for the differentiation of T-helper (Th) cells into particular Th lineage subsets. How STAT-mediated Th cel...
STAT transcription factors are activated by tyrosine phosphorylation after cytokine stimulation and are critical for the differentiation of T-helper (Th) cells into particular Th lineage subsets. How STAT-mediated Th cell differentiation is negatively regulated, however, is not fully understood. Here, we report that PDLIM4 binds to STAT3, 4, and 6 and suppresses gene activation mediated by these STATs. PDLIM4 acts as an adaptor that recruits PTP-BL, a protein tyrosine phosphatase, through its LIM domain, facilitating dephosphorylation of STAT proteins. PDLIM4-deficiency in CD4+ T cells resulted in augmented tyrosine phosphorylation of these STAT proteins and consequently enhanced Th1, Th2 and Th17 cell differentiation, suggesting that PDLIM4 regulates the differentiation of multiple lineages of Th cells by suppressing STAT signaling. We further found that a non-synonymous single-nucleotide polymorphism (nsSNP) in PDLIM4, which causes the substitution of a glycine residue with a cysteine in the LIM domain, is associated with susceptibility to rheumatoid arthritis and Graves' disease, both of which are known to be Th17 cell-driven autoimmune diseases. Notably, PDLIM4 containing this amino acid substitution in the LIM domain showed reduced binding to PTP-BL and was therefore partially impaired in its ability to dephosphorylate STAT3 and suppress STAT3 signaling. Our findings define an essential role of PDLIM4 in negatively regulating STAT-mediated T helper cell differentiation and preventing the onset of human autoimmune diseases.
Lipid metabolic regulation of pathogenic type 2 immunity in the airway.
Yagyu H, Kiuchi M, Hirahara K
Int Immunol · 2026 Apr · PMID 41990290 · Publisher ↗
Immune memory is central to host protection against pathogens and contributes to the pathogenesis of chronic inflammatory diseases. Beyond canonical cytokines and antigenic stimuli, metabolic signals have emerged as pivo...
Immune memory is central to host protection against pathogens and contributes to the pathogenesis of chronic inflammatory diseases. Beyond canonical cytokines and antigenic stimuli, metabolic signals have emerged as pivotal regulators of T-cell activation, differentiation, and memory formation. However, the mechanisms by which metabolic and tissue-derived cues imprint pathogenic features on T cells remain poorly understood. Dysregulation of type 2 immune memory is a major driver of chronic inflammation in allergic diseases. A distinct subpopulation of memory T helper 2 (Th2) cells that express the interleukin (IL)-33 receptor ST2 has emerged as a key contributor to the pathogenesis of chronic allergic inflammation. Recent studies have revealed a close link between lipid metabolism and pathogenic type 2 immunity, highlighting how fatty acid uptake, storage within lipid droplets, and catabolism through lipolysis and lipophagy regulate the expression of ST2 and cytokine production. Moreover, transcriptional regulators such as peroxisome proliferator-activated receptor γ (PPARγ) integrate lipid-derived signals with transcriptional and metabolic programs that induce pathogenic memory. In this review, we summarize the current understanding of CD4+ T cell-mediated immune memory, with a particular focus on pathogenic Th2 cells and airway type 2 immunity, and discuss emerging concepts that connect lipid metabolic programs, transcriptional regulation, and chronic allergic inflammation.
Multiple evolutionary routes to immune diversification across animals.
Taguchi M, de La Forest Divonne S, Morimoto R
Int Immunol · 2026 Apr · PMID 41982100 · Publisher ↗
Adaptive immunity is often viewed as a defining innovation of vertebrates, characterized by somatically diversified antigen-receptors and clonal lymphocyte lineages. Yet the evolutionary origins of such systems remain in...
Adaptive immunity is often viewed as a defining innovation of vertebrates, characterized by somatically diversified antigen-receptors and clonal lymphocyte lineages. Yet the evolutionary origins of such systems remain incompletely understood. In this review, we examine adaptive immunity from a comparative perspective across Metazoa, focusing on the design principles that link molecular diversification, immune cell differentiation, and proliferative dynamics. We first outline the two adaptive immune architectures found in vertebrates. Jawed vertebrates employ immunoglobulin-based and T cell receptor (TCR)-based recognition generated through RAG-mediated V(D)J recombination, whereas jawless vertebrates assemble variable lymphocyte receptors using cytidine-deaminase-dependent diversification of leucine-rich-repeat modules. Despite their distinct molecular entities, these systems converge on shared design principles, including somatic diversification, developmental restriction of genome editing, immune cell differentiation, and specialized microenvironments for immune education. To introduce evolutionarily more ancient systems, several diversification mechanisms of antigen-receptors in invertebrates will be subsequently surveyed. These systems generate substantial molecular diversity without canonical clonal selection, suggesting that immune recognition and diversification can be achieved through multiple evolutionary strategies. Particular attention is given to emerging insights into invertebrate immune cell diversification, where single-cell transcriptomics is revealing complex hematopoietic lineages and regulatory programs. These observations suggest that adaptive immunity did not emerge abruptly but rather represents one solution within a broader evolutionary landscape of immune diversification strategies. Understanding how diversification, proliferation, and cellular organization interact across animal lineages will help clarify the fundamental design constraints that shaped the evolution of vertebrate adaptive immune systems.
RNF213-TRAF2 interaction enhances inflammatory responses via NF-κB activation in moyamoya disease.
Yasuda M, Murakami K, Jiang JJ … +12 more , Ito M, Tanaka Y, Tanaka H, Hasebe R, Yamasaki T, Hashimoto A, Kubota SI, Hojyo S, Atsumi T, Hashimoto S, Murakami M, Fujimura M
Int Immunol · 2026 Mar · PMID 41891799 · Publisher ↗
Moyamoya disease (MMD) is a cerebrovascular disorder that predominantly affects East Asian populations. It is characterized by progressive stenosis or occlusion of terminal internal carotid arteries. Although inflammator...
Moyamoya disease (MMD) is a cerebrovascular disorder that predominantly affects East Asian populations. It is characterized by progressive stenosis or occlusion of terminal internal carotid arteries. Although inflammatory and autoimmune responses have been implicated in MMD pathogenesis, the precise molecular mechanisms underlying the disease remain poorly understood. RNF213, a key susceptibility gene for MMD, has been linked to inflammatory signaling; however, its role in NF-κB-driven inflammation remains unclear. Here, we identify RNF213 as a critical regulator of the IL-6 amplifier (IL6-Amp), a mechanism that enhances NF-κB-mediated inflammation in the presence of IL-6-STAT3 in non-immune cells. RNF213 knockdown reduced IL-6 expression in H4 cells, a model for IL6-Amp induction via tumor necrosis factor (TNF)-α and IL-6 co-stimulation, selectively suppressing NF-κB target genes. In vivo, RNF213 depletion attenuated inflammation in an NF-κB-dependent imiquimod-induced ear swelling model. The MMD-associated RNF213 p.R4810K variant enhanced NF-κB activation by strengthening the interaction between RNF213 and TRAF2, a key adaptor in TNF-α-NF-κB signaling. Consistent with these findings, histopathological analysis of superficial temporal arteries from MMD patients revealed genotype-dependent IL6-Amp activation, with pronounced phosphorylation of NF-κB p65 and STAT3 in homozygous carriers. In contrast, heterozygous and wild-type vessels showed minimal basal activation, but in vitro stimulation of arachnoid cells from a heterozygous patient recapitulated IL6-Amp responsiveness. Collectively, these findings establish RNF213 as a pivotal regulator of NF-κB-driven inflammation and suggest that the p.R4810K variant amplifies inflammatory signaling, thereby contributing to MMD pathogenesis. This study not only advances our understanding of MMD pathophysiology but also highlights potential therapeutic strategies targeting inflammation.
ELAVL1 modulates periodontal ligament fibroblast pyroptosis in periodontitis through the JAK2/STAT3/NLRP3 axis.
Zhan H, Shi G, Xie Q … +2 more , Chen Y, Zhang Y
Int Immunol · 2026 Mar · PMID 41838803 · Publisher ↗
Periodontitis is an inflammatory disorder that leads to the destruction of periodontal tissues. Pyroptosis, related to the NLRP3 inflammasome, is implicated in the pathogenesis of periodontitis. ELAVL1, an m6A reader, is...
Periodontitis is an inflammatory disorder that leads to the destruction of periodontal tissues. Pyroptosis, related to the NLRP3 inflammasome, is implicated in the pathogenesis of periodontitis. ELAVL1, an m6A reader, is associated with inflammatory responses; however, its role in periodontitis requires further clarification. Our research elucidated the regulatory functions of ELAVL1 in periodontitis and explored the underlying mechanisms. Expression of ELAVL1 in periodontitis mice and P.g-LPS-induced PLFs was assessed via qRT-PCR and western blot. ELISA was performed to analyze IL-1β and IL-18 levels. The associated protein levels of the NLRP3 inflammasome, bone formation, and JAK2/STAT3 pathway were detected using western blot. Pyroptosis was evaluated by flow cytometry. RIP, MeRIP, and dual-luciferase reporter assay were performed to validate the association between ELAVL1 and JAK2 mRNA. Immunofluorescence was used to detect ELAVL1, NLRP3 and Vimentin expression in periodontal tissues. The pathological changes in periodontal tissues were determined by micro-CT and H&E staining. We found that ELAVL1 was upregulated in periodontitis tissues and P.g-LPS-stimulated PLFs. Mechanistically, ELAVL1 bound to JAK2 mRNA, enhancing its m6A modification and stability, thereby activating the JAK2/STAT3 signaling. Knockdown of ELAVL1 decreased NLRP3 inflammasome activation and pyroptosis in PLFs, inhibited inflammatory factor secretion, and inhibited activation of the JAK2/STAT3 pathway. However, these effects were partially reversed following treatment with C-A1. Furthermore, ELAVL1 knockdown attenuated alveolar bone loss, decreased p-JAK2 and p-STAT3 levels, and suppressed NLRP3-mediated pyroptosis in vivo. We conclude that ELAVL1 promotes periodontitis by mediating m6A modification of JAK2 and activating the JAK2/STAT3/NLRP3-mediated pyroptosis, suggesting its promise as a novel treatment target for periodontitis.
Overexpression of the transcriptional corepressor Tle1 enhances effector proliferation of CD8+ T cells during acute and chronic viral infections.
Shiga R, Fujisawa S, Tanabe Y … +4 more , Kurachi J, Koura M, Tamai T, Kurachi M
Int Immunol · 2026 Jun · PMID 41810855 · Publisher ↗
The transcriptional corepressor Tle (transducin-like enhancer of split) proteins interact with transcription factors such as TCF-1 and Runx3 to regulate transcriptional programmes during cellular development and differen...
The transcriptional corepressor Tle (transducin-like enhancer of split) proteins interact with transcription factors such as TCF-1 and Runx3 to regulate transcriptional programmes during cellular development and differentiation; however, their roles in CD8+ T cell differentiation, particularly under conditions of chronic antigen stimulation, remain poorly defined. Here, we demonstrated that overexpression of Tle1, Tle3, and Tle4 improves the proliferation of antigen-specific effector CD8+ T cells during both acute and chronic viral infections. Notably, overexpression of Tle3 and Tle4, but not Tle1, augmented secondary responses of memory CD8+ T cells in the context of acute viral infection. Tle1-overexpressing CD8+ T cells displayed enhanced TCR signal strength, accompanied by elevated expression of immunoinhibitory receptors such as PD-1 and LAG-3. Transcriptome analyses and genome-wide binding profiles suggested that Tle1 and Tle3 cooperate with multiple transcription factors, including members of the Ets, AP-1, and Runx families, to drive expression of genes involved in the activation and maintenance of antigen-specific CD8+ T cell responses. Notably, Tle1 overexpression improves cytotoxic T lymphocyte (CTL) responses to PD-1/PD-L1 blockade during chronic viral infection. Tle1 was found to enhance TCR signalling and the expression of immunoinhibitory receptors through repression of TCF-1, whereas its effect on effector CD8+ T cell proliferation occurred independently of TCF-1. These findings revealed the regulatory roles of Tle proteins in orchestrating transcription factor networks that govern CD8+ T cell differentiation during viral infections.
Association between autoimmune diseases and the gut microbiome.
Hirano Y, Tomofuji Y, Edahiro R … +3 more , Kishikawa T, Miyawaki S, Okada Y
Int Immunol · 2026 Jul · PMID 41810506 · Publisher ↗
The gut microbiome has emerged as an important environmental factor in the pathogenesis of autoimmune diseases. Advances in high-throughput sequencing technologies have enabled comprehensive characterization of the gut m...
The gut microbiome has emerged as an important environmental factor in the pathogenesis of autoimmune diseases. Advances in high-throughput sequencing technologies have enabled comprehensive characterization of the gut microbiome, providing detailed insights into its composition and functional potential. These approaches have been widely applied in autoimmune disease research, revealing disease-associated alterations in the gut microbiome of patients with conditions such as rheumatoid arthritis and systemic lupus erythematosus. In addition, microbiome sequencing data can be leveraged to investigate the gut virome, including viruses residing in the intestinal ecosystem. This review summarizes current evidence linking autoimmune diseases and the gut microbiome, with a particular focus on studies employing microbiome sequencing-based analyses.
Single-cell RNA-sequencing of myasthenia gravis reveals transcriptional heterogeneity and dysfunction of immune cell populations.
Wu Q, Guo Y, Zhou L … +5 more , Tian Y, Yu H, Zhou T, Yin S, Zou L
Int Immunol · 2026 Jul · PMID 41758503 · Full text
The purpose of this study was to explore the composition and function of immune cell subsets at the single-cell level in the thymus and peripheral blood of patients with myasthenia gravis (MG). A total of 9701 and 23 846...
The purpose of this study was to explore the composition and function of immune cell subsets at the single-cell level in the thymus and peripheral blood of patients with myasthenia gravis (MG). A total of 9701 and 23 846 cells, respectively, originated from the peripheral blood and thymus samples of two MG patients, and 6930 cells from the peripheral blood of two gender- and age-matched healthy controls (HCs) were selected for single-cell RNA-sequencing. Uniform manifold approximation and projection (UMAP), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Monocle3, and Velcyto were performed to analyze the composition, molecular and functional properties, and developmental trajectory of immune cell subsets. Four major cell populations of T cells, B cells, myeloid cells, and natural killer cells were identified, as well as their 15 cell subpopulations. An absolute predominance of T cells was found in the thymus and peripheral blood of MG patients, and the proportions of memory B cells in both plasma and thymus showed an increasing trend while the number of naïve B cells demonstrated a decreasing trend in MG patients compared with HCs. Besides, the monocytes in the peripheral blood of MG patients had the strongest interactions with other cells. Furthermore, CXCL, GAS, and CD30 signaling pathways were more enriched within MG peripheral blood. Our research clarifies the cellular heterogeneity in the pathogenesis of MG and characterizes the immune microenvironment of thymic tissues in MG patients.
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