International Immunology[JOURNAL]
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200 papers
Functional diversity and tissue-specific regulation of Group 2 innate lymphoid cells in barrier immunity.
Ito M, Yan Y, Satoh-Takayama N
Int Immunol · 2026 Apr · PMID 41059765 · Publisher ↗
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...
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.
Interaction between neurons and microglia in healthy and disease states.
Nakamura A, Shichita T
Int Immunol · 2026 Mar · PMID 41001810 · Publisher ↗
Interactions between neurons and microglia are essential for various brain functions under both healthy and pathological states. Microglia have classical functions as immune cells, causing cerebral inflammation, whereas...
Interactions between neurons and microglia are essential for various brain functions under both healthy and pathological states. Microglia have classical functions as immune cells, causing cerebral inflammation, whereas their reparative roles after acute cerebral inflammation have recently attracted attention. In the healthy brain state, microglia contribute to homeostasis and brain tissue development. Microglia regulate neuronal activity by responding to molecules derived from neurons and eliminating excess synapses to achieve normal brain development and maintain a homeostatic brain environment. Microglia are also involved in neuronal information processing, such as learning and memory, by modulating synaptic remodeling and neurogenesis. In contrast, aging alters brain homeostasis and increases vulnerability to neurodegenerative pathologies through changes in interactions between neurons and microglia. Microglia exert diverse functions in neurological and psychiatric diseases. Microglia are responsible for rapid inflammatory responses by receiving abnormal signals from injured brain cells. Excess neuroinflammation mediated by disease-associated microglia exacerbates the pathology of central nervous system (CNS) diseases. Recent studies have also revealed the roles of microglia in improving pathologies through the phagocytosis of neurotoxic proteins and damaged or excess synapses. This review highlights the interaction between neurons and microglia in both healthy and pathological brain states. Understanding these interactions could lead to the development of therapeutic strategies by regulating the pathologies underlying various CNS disorders.
Neuroprotective crosstalk from vitamin B12 and sphingolipid signaling pathways in therapy for multiple sclerosis.
Kihara Y, Chun J
Int Immunol · 2026 Mar · PMID 40994054 · Full text
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) characterized by neuroinflammation, demyelination, and neurodegeneration. Among disease-modifying therapies, sphingo...
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) characterized by neuroinflammation, demyelination, and neurodegeneration. Among disease-modifying therapies, sphingosine 1-phosphate (S1P) receptor (S1PR) modulators such as fingolimod, also known as FTY720, have been shown to exert therapeutic effects through direct CNS actions at S1PRs (e.g. S1P1) expressed by astrocytes, beyond the originally proposed mechanism action of lymphocyte sequestration. This review highlights the emerging evidence linking S1P signaling to the vitamin B12 pathway, including transcobalamin 2 (TCN2) and CD320. Functional interaction between S1P1 signaling and CD320 expression was discovered by examining gene expression changes in immediate-early astrocytes (ieAstrocytes), the primary CNS cell type activated in response to neuroinflammatory stimuli. This discovery led to the identification of the physical interaction between fingolimod/sphingosine and TCN2 and the potentiation of CD320 internalization by this complex. These findings underscore the importance of CNS vitamin B12 levels in MS and likely other neurological diseases and help to explain the long-appreciated shared neurological symptoms between vitamin B12 deficiency and MS. Future research should investigate therapeutic strategies targeting the crosstalk between the sphingolipid and vitamin B12 pathways to enhance CNS vitamin B12 availability, which can promote neuroprotection in MS and related diseases.
Direct analysis of hepatic stellate cells with flow cytometry in specimens derived from the human liver.
Bando T, Sato H, Uno S … +12 more , Morita H, Zreka L, Ma S, Khan M, Akuzawa D, Masuo Y, Matsuyama J, Nishida R, Okumura S, Hatano E, Ito T, Ueno H
Int Immunol · 2026 Feb · PMID 40973177 · Publisher ↗
Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis. However, the methodology to directly assess the biology of primary HSCs in human liver specimens is yet to be established. In this study, we aimed to e...
Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis. However, the methodology to directly assess the biology of primary HSCs in human liver specimens is yet to be established. In this study, we aimed to establish a robust methodology to analyse primary HSCs in human liver specimens with flow cytometry (FCM). We first applied FCM to HSCs directly isolated from liver tissues with Nycodenz density gradients. Then, we analysed HSCs in frozen/thawed liver perfusate samples and liver tissues. We also compared the phenotype of HSCs in primary biliary cholangitis (PBC) and those in healthy counterparts. We found that HSCs were substantially smaller and less dense than normal lymphocytes in the FCM analysis. By carefully defining the FCM gating strategy, we were able to establish the approach to analyse both quiescent HSCs (qHSCs) and activated HSCs (aHSCs) in human liver specimens. Importantly, we found that co-expression of CD14 and CD56 within CD45 non-immune cells permits the detection of qHSCs, whereas CD68 and CD40 within CD45 non-immune cells were valuable for assessing aHSCs. Furthermore, we found that aHSCs in PBC upregulated the expression of multiple markers associated with antigen-presentation capacity. Our established approach with FCM will be valuable for the direct analysis of qHSCs and aHSCs with FCM in various human liver specimens. Our FCM analysis of aHSCs in PBC suggested their involvement in the local immune responses.
The chitosan nanoparticle-based adjuvant CH-100 orchestrates multifaceted innate immune activation via STING-dependent and -independent pathways.
Nagai E, Ori D, Kano N … +5 more , Ikegawa M, Kobiyama K, Ishii KJ, Kawasaki T, Kawai T
Int Immunol · 2026 Feb · PMID 40973173 · Publisher ↗
Adjuvants enhance vaccine efficacy by activating innate immunity; yet, the mechanisms of nanoparticle-based adjuvants remain incompletely defined. Here, we characterize CH-100, a chitosan nanoparticle adjuvant, and its c...
Adjuvants enhance vaccine efficacy by activating innate immunity; yet, the mechanisms of nanoparticle-based adjuvants remain incompletely defined. Here, we characterize CH-100, a chitosan nanoparticle adjuvant, and its capacity to coordinate dendritic cell (DC) activation and promote adaptive immune responses. CH-100 enhances antigen uptake, upregulates co-stimulatory molecules, and elicits antigen-specific antibody and cytotoxic T lymphocytes (CTL) responses. Mechanistically, CH-100 induces mitochondrial reactive oxygen species (ROS), leading to NLRP3 inflammasome activation, although NLRP3 is not essential for the observed adaptive responses. In parallel, CH-100 triggers the STING-IRF3 pathway to induce type I interferons; STING-deficiency partially diminishes antibody and CTL responses, suggesting involvement of additional signaling. Transcriptomic analysis reveals STING-independent upregulation of genes related to Th17 differentiation, accompanied by activation of TBK1, NF-κB, and p38 pathways in DCs, ultimately promoting Th17-skewed immunity. These findings demonstrate how CH-100 engages both STING-dependent and -independent innate pathways to shape adaptive immunity, offering mechanistic insights into chitosan-based adjuvants for future vaccine development.
Oligoclonal expansion of IgG+ B cells along with Tfh cell response is associated with a better outcome in endometrial cancer.
Fujioka M, Fujioka S, Yoshitomi H … +8 more , Hamanishi J, Suzuki H, Ukita M, Takeuchi Y, Minamiguchi S, Ito H, Mandai M, Ueno H
Int Immunol · 2026 Jan · PMID 40916279 · Publisher ↗
B cells play a critical role in tumor immunity, with their presence associated with improved prognosis in various cancers, including endometrial cancer (EC). However, the nature of the B-cell response within the tumor mi...
B cells play a critical role in tumor immunity, with their presence associated with improved prognosis in various cancers, including endometrial cancer (EC). However, the nature of the B-cell response within the tumor microenvironment (TME) remains incompletely understood. In this study, we conducted single-cell analyses of B cells and CD4+ T cells in the TME of EC. We found that the TME of EC harbored abundant plasmablasts and plasma cells (PCs), which were rare in normal endometria. PCs primarily expressed either IgG or IgA, and a high abundance of IgG in TME was associated with better overall survival. B-cell receptor (BCR) repertoire analysis revealed a clonal expansion of IgG+ B cells, coinciding with an increased presence of T follicular helper (Tfh) cells in the TME. Notably, Tfh cells shared T-cell receptor clones with cycling CD4+ T cells, indicating local proliferation. BCR repertoire analysis also suggested that IgG+ PCs differentiate from IFN-responding B cells and double-negative B cells in the TME. Additionally, recombinant oligoclonal IgG antibodies were found to recognize antigens expressed by tumor cells as well as normal endometrial cells. Collectively, our study shows that the clonal expansion of IgG+ B cells, along with the Tfh cell response, is associated with a better outcome in EC.
Anti-human TLR7 antibody for therapeutic intervention in systemic lupus erythematosus.
Fukui R, Murakami Y, Kanno A … +14 more , Motoi Y, Manno A, Honda T, Yamada S, Ishiguro J, Kagari T, Nakamura K, Kadokura M, Isobe T, Tomimori Y, Tanaka J, Senaldi G, Shimizu T, Miyake K
Int Immunol · 2026 Jan · PMID 40910948 · Full text
Toll-like receptor 7 (TLR7) is an endosomal sensor that responds to both pathogen-derived and self-derived single-stranded RNA (ssRNA). Responses of TLR7 to self-derived ssRNA have been implicated in the development of a...
Toll-like receptor 7 (TLR7) is an endosomal sensor that responds to both pathogen-derived and self-derived single-stranded RNA (ssRNA). Responses of TLR7 to self-derived ssRNA have been implicated in the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). TLR7 antagonists and inhibitory anti-TLR7 monoclonal antibodies (mAbs) can protect lupus-prone NZBWF1 mice from lethal nephritis. However, less is known about TLR7 dependence and activation in human SLE, as both TLR7 and TLR8 respond to ssRNA in humans. Here, we analyzed public databases and found that TLR7 gene signature scores were consistently elevated across datasets, races, and SLEDAI scores compared to TLR8, suggesting a deeper involvement of TLR7 in SLE pathogenesis. To specifically inhibit human TLR7 responses, we developed inhibitory mAbs against human TLR7. Utilizing an inhibitory clone, we generated the humanized mAb, DS-7011a. DS-7011a effectively inhibited TLR7-mediated responses in plasmacytoid dendritic cells (pDCs) and B cells. Furthermore, DS-7011a was internalized in a TLR7-dependent manner and accumulated in B cells, pDCs, conventional dendritic cells (cDCs), and monocytes/macrophages. In this study, we describe the generation and preclinical development of DS-7011a, which has the potential to be a therapeutic option for the treatment of SLE.
Role of Themis in peripheral CD8 T cells in hapten-induced allergic skin inflammation.
Kitajima M, Okada T, Nakano K … +2 more , Okamura T, Suzuki H
Int Immunol · 2026 Feb · PMID 40887931 · Publisher ↗
Themis (thymocyte-expressed molecule involved in selection) is a T-cell-specific protein that is critically required for positive selection in the thymus. However, its function in T-cell receptor (TCR) responses during a...
Themis (thymocyte-expressed molecule involved in selection) is a T-cell-specific protein that is critically required for positive selection in the thymus. However, its function in T-cell receptor (TCR) responses during allergic skin inflammation remains unclear. To investigate the function of Themis in peripheral T cells, we generated tamoxifen-induced Themis conditional knockout (cKO) mice. The deletion of Themis by tamoxifen treatment significantly reduced ear swelling and CD8 T-cell infiltration induced by hapten 2,4-dinitrofluorobenzene (DNFB) challenge, which activates CD8 T cells. The CD8 T cells in the inflamed skin from Themis cKO mice showed decreased interferon gamma (IFNγ) production and T-bet and Eomes expression. Furthermore, the transgenic overexpression of Themis enhanced DNFB-induced allergic skin responses. However, Themis cKO mice showed unaltered skin inflammation induced by fluorescein isothiocyanate/dibutyl phthalate, which activates CD4 T cells. The TCR-stimulated proliferation and IFNγ production of Themis cKO naïve CD8 T cells were significantly decreased in vitro, whereas the proliferation and cytokine production of CD4 T cells were not altered. As expected, the administration of the SHP-1/2 inhibitor restored the reduced IFNγ production in Themis cKO CD8 T cells in vitro. Mice harboring mutant Themis lacking the Grb2-binding site showed a similar phenotype to Themis cKO mice, indicating that the function of Themis in peripheral CD8 T cells is dependent on Grb2 binding. Collectively, these results suggest that Themis regulates the threshold of TCR signaling in peripheral CD8 T cells, but not in CD4 T cells.
Vaccine adjuvants as stand-alone immunoprophylaxis in strategies for 100-day rapid responses to future pandemics.
Kavian N, Kobiyama K, Ishii KJ … +1 more , Coban C
Int Immunol · 2026 Feb · PMID 40884464 · Publisher ↗
The COVID-19 pandemic accelerated vaccinology progress, driving rapid vaccine development for infectious and non-infectious diseases. However, challenges persist: malaria, HIV, and dengue lack fully effective vaccines, w...
The COVID-19 pandemic accelerated vaccinology progress, driving rapid vaccine development for infectious and non-infectious diseases. However, challenges persist: malaria, HIV, and dengue lack fully effective vaccines, whereas influenza and tuberculosis face waning efficacy. Emerging pathogens and drug-resistant strains further highlight the need for improved vaccines, particularly those offering rapid deployment, broad immunogenicity, and durable protection against variants. Adjuvants can play a dual role in this context: as new stand-alone tools for an early response to a pandemic-aiming at the 100-day mission objective-and for prevention of antimicrobial resistance; and as traditional components enhancing the efficacy and breadth of vaccines. The understanding of their mechanisms of action and novel usage could address critical gaps in pandemic preparedness, especially for vulnerable populations like children and the elderly.
Molecular mechanisms for direct sensing of virus-like antigens by B cells.
Cheng W, Zikherman J
Int Immunol · 2026 Feb · PMID 40884252 · Full text
Particulate antigens (Ags) such as viruses can often induce strong B-cell responses in vivo very effectively, but the molecular determinants of this complex process remain incompletely understood. In this review, we focu...
Particulate antigens (Ags) such as viruses can often induce strong B-cell responses in vivo very effectively, but the molecular determinants of this complex process remain incompletely understood. In this review, we focus on recent mechanistic insights into the earliest steps in the initiation of primary B-cell responses to viruses, gained by exploiting a new generation of model particulate Ag, synthetic virus-like structures. We also review the characteristics of the resulting short- and long-term antibody (Ab) responses in mice. These studies reveal that a repeating pattern of epitope display on a virus-sized scaffold is a fundamental biophysical feature of viruses that triggers a qualitatively distinct mode of B-cell Ag receptor (BCR) signal transduction relative to soluble Ag display, and consequently serves as a standalone danger signal for Ag-specific B-cell activation. Quantitative variation in epitope density (ED) on such scaffolds modulates the degree and quality of B-cell activation both in vitro and in vivo. The presence of internal nucleic acid (iNA) in the interior of these virus-like structures can profoundly influence the resulting Ab responses for the lifespan of immunized animals. We conclude that the ED of viral surface Ags and the iNA genomes provide two essential signals that together are sufficient for B-cell activation and Ab production during antiviral responses. We place these findings in the context of the literature, discuss implications for rational vaccine design, and highlight unanswered questions to guide future research directions.
The role of IL-4+ memory T cells in SARS-CoV-2 booster vaccination.
Khalil J, Miyauchi K, Suzuki Y … +15 more , Ki S, Harada Y, Sasaki T, Yamamoto Y, Hashimoto R, Yamamoto T, Matsuda M, Koseki H, Nakayama M, Fukasawa M, Wakita T, Ueno H, Noguchi K, Takayama K, Kubo M
Int Immunol · 2026 Jan · PMID 40884220 · Publisher ↗
Vaccines effectively stimulate protective immune responses in healthy individuals, but the precise roles of germinal center (GC) and follicular helper T (TFH) cells in severe acute respiratory syndrome coronavirus 2 (SAR...
Vaccines effectively stimulate protective immune responses in healthy individuals, but the precise roles of germinal center (GC) and follicular helper T (TFH) cells in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine responses are not fully understood. This study used a conditional loss-of-function mouse model to investigate antibody responses to the Wuhan spike protein, specifically eliminating newly developed TFH cells during either the primary or memory phase. Our findings demonstrated that TFH-mediated GC responses are essential for primary vaccination. However, after booster immunization, memory B-cell responses were effectively regulated through extrafollicular mechanisms, independent of TFH cells. Ablating IL-4 receptor signaling in B cells attenuated antibody production in both the primary and memory phases, highlighting the critical role of IL-4 for optimal humoral immunity. We identified a unique population of IL-4-expressing memory T (IL-4+Tm) cells, characterized by CD27, GATA3, and IRF4 expression, that is strongly associated with these extrafollicular memory B-cell responses, capable of neutralizing SARS-CoV-2 variants. Furthermore, Omicron-based booster immunization recovered the immunity against emerging variants under TFH-deficient conditions. These results suggest that IL-4+Tm cells are an alternative pathway to sustain memory responses when GC function is impaired, particularly in immunocompromised states. Our study advances the understanding of memory T-cell-mediated humoral responses to SARS-CoV-2, offering insights for future vaccine strategies.
The thyroid hormone receptor beta (TR-β) signaling controls pathogenic Th17 cells in autoimmune disease.
Doi Y, Raveney BJE, Kimura A … +5 more , Mallahalli MS, Kimura K, Sato W, Oki S, Yamamura T
Int Immunol · 2025 Dec · PMID 40873150 · Publisher ↗
The role of the thyroid hormone receptor beta (TR-β) in the immune system remains poorly understood; although its effect on TGF-β signaling has been reported in nonimmune systems. Here, we report that Thrb is highly expr...
The role of the thyroid hormone receptor beta (TR-β) in the immune system remains poorly understood; although its effect on TGF-β signaling has been reported in nonimmune systems. Here, we report that Thrb is highly expressed in pathogenic CD4+ T cells that infiltrate the central nervous system during experimental autoimmune encephalomyelitis (EAE), and Thrb is exclusively expressed in IL-17-producing CD4+ T cells (Th17 cells) that develop both in vitro or in vivo. Sobetirome, a selective TR-β agonist, promoted pathogenic Th17 differentiation and IL-17 production in the presence of exogenous IL-1β. Conversely, small interfering RNA (siRNA)-mediated silencing of TR-β reduced IL-17 production, further supporting a T cell-intrinsic role of TR-β. Because C75, an inhibitor of de novo lipogenesis, blocked Th17 cell differentiation by sobetirome, the influence of TR-β signaling on Th17 cell induction is likely to act via a de novo lipogenesis-dependent mechanism. Furthermore, blocking TR-βexpression by siRNA changed the balance of IL-10/IL-17 production in cultured splenocytes, favoring an IL-10 phenotype. In contrast, IL-10 production by T cells was attenuated by activating TR-β signaling with sobetirome. Finally, the manipulation of TR-β signaling altered the severity of autoimmune disease: blocking TR-β reduced passive EAE and enhancing TR-β increased active EAE. These effects were accompanied by corresponding changes in the IL-10/IL-17 balance in encephalitogenic CD4+ T cells. In summary, our results demonstrate that TR-β signaling controls pathogenic Th cell function and autoimmunity.
TCR representation learning with protein language models: a comprehensive review.
Kinoshita K, Kobayashi TJ
Int Immunol · 2026 Jan · PMID 40855636 · Full text
The T-cell receptor (TCR) repertoire is a valuable source of information that reflects an individual's immune status and infection history. However, due to the exceptional diversity and complexity of the TCR repertoire,...
The T-cell receptor (TCR) repertoire is a valuable source of information that reflects an individual's immune status and infection history. However, due to the exceptional diversity and complexity of the TCR repertoire, predicting its functional properties remains a challenging task. This review summarizes recent advances in protein language models (PLMs), which apply natural language processing techniques to protein sequences, focusing specifically on TCR repertoire analysis. We begin by outlining the biological basis of the TCR repertoire and its current clinical applications. We then describe the methods used for representing TCR data and the training procedures of the corresponding PLMs. PLMs capture context-dependent features from large unlabeled TCR datasets and achieve high generalization performance even with limited labeled data through transfer learning. In this respect, PLMs offer significant advantages over conventional sequence representation methods. We highlight antigen specificity prediction as a key application, comparing supervised deep learning models with PLM-based approaches. While employment of PLMs is promising, TCR repertoire analysis still faces challenges such as data scarcity, bias, and lack of paired-chain information. Addressing these challenges requires rigorous dataset optimization, integration, and augmentation strategies. Future advances will require better interpretation of the representations learned by PLMs and the development of multimodal approaches that integrate structural information. These advances could enable several clinical applications, including disease diagnosis, vaccine development, and personalized immune profiling.
Correction to: Correlation of interferons and autoimmune aspects in long COVID-19 patients.
Int Immunol · 2025 Sep · PMID 40796217 · Full text
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Folic acid supplementation during pregnancy alleviates food allergy in offspring by inhibiting mast cell degranulation.
Wang Q, Jiang Y, Duan S … +4 more , Szeto IM, Che H, Liu C, Guo X
Int Immunol · 2025 Dec · PMID 40747647 · Publisher ↗
Studies have been exploring the connection between the intake of vitamins and the development of food allergy, with a particular focus on folic acid (FA). However, the impact of FA supplementation on food allergy remains...
Studies have been exploring the connection between the intake of vitamins and the development of food allergy, with a particular focus on folic acid (FA). However, the impact of FA supplementation on food allergy remains a subject of debate. In the present study, the anti-allergic properties of FA and its possible mechanism of action were investigated. In a Brown Norway rat food allergy model, we found that FA downregulated the expression of specific antibodies, while influencing the Th1/Th2 balance. Furthermore, FA was found to reduce the release of particulate matter such as histamine and mast cell proteinase. Transcriptomic analysis provided evidence that FA intervention could reverse gene expression changes induced by food allergies. The gene Hsp90, responsible for producing heat shock proteins (HSP), emerged as a potential key gene involved in the process. In vitro RBL-2H3 cell-based assays suggested that FA might affect HSP90 expression through the glucocorticoid receptor (GR), leading to a reduction in effector cell degranulation. Overall, the results of this study indicate that FA has an alleviating effect on food allergies, with high doses of FA exhibiting more pronounced effects. Moreover, FA's impact on HSP90 expression through GR seems to contribute to a decrease in degranulation during the effector phase.
Interleukin-35 regulates the differentiation of regulatory T cells through the JAK-STAT pathway and influences glutamine metabolism in ARDS.
Peng QZ, Zhang M, Zhang AP … +7 more , Guo MK, Luo RJ, Zeng L, Chen C, Lin SH, Xu F, Xie K
Int Immunol · 2025 Nov · PMID 40643216 · Publisher ↗
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 sam...
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.
Epigenomic control of immunity: from mechanisms to therapeutic targets in inflammatory bowel diseases.
Shih HY, Sciumè G, Mikami Y
Int Immunol · 2025 Dec · PMID 40627746 · Full text
This review presents an overview of the emerging roles of epigenomic regulation in immune cell function, with a particular focus on its relevance in inflammatory bowel diseases (IBD). Epigenetic mechanisms, including DNA...
This review presents an overview of the emerging roles of epigenomic regulation in immune cell function, with a particular focus on its relevance in inflammatory bowel diseases (IBD). Epigenetic mechanisms, including DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs, are essential in directing immune cell development, activation, and lineage commitment. Advances in genomics and epigenomics have highlighted the dynamic nature of gene regulation as the cornerstone of immune homeostasis and adaptability. We summarize recent insights into enhancer dynamics, three-dimensional chromatin architecture, transcription factor signaling, and microRNA (miRNA)-mediated regulation that reshape our understanding of immune-mediated diseases. These findings not only deepen our knowledge of disease pathogenesis but also offer promising targets for therapeutic intervention. In this context, miRNAs have emerged as key post-transcriptional regulators with significant diagnostic and therapeutic potential for IBD. The field of immune epigenomics is advancing rapidly, offering powerful tools for dissecting complex immune responses and guiding the development of precise therapies for chronic inflammatory conditions.
TREX1 exonuclease in immunity and disease.
Shang Z, Wang L, Zhou W
Int Immunol · 2025 Dec · PMID 40627703 · Publisher ↗
Three-prime repair exonuclease 1 (TREX1) is the major 3' to 5' DNA exonuclease in mammals and plays an essential role in preserving immune homeostasis by controlling cytosolic DNA sensing. By degrading excess self and fo...
Three-prime repair exonuclease 1 (TREX1) is the major 3' to 5' DNA exonuclease in mammals and plays an essential role in preserving immune homeostasis by controlling cytosolic DNA sensing. By degrading excess self and foreign DNA, TREX1 limits aberrant activation of the cGAS-STING (cyclic GMP-AMP synthase - stimulator of interferon genes) pathway and downstream type I interferon responses. Loss-of-function mutations in TREX1 underlie a spectrum of interferon-driven autoimmune and autoinflammatory syndromes, demonstrating its role as a key regulator of immune tolerance. Beyond autoimmunity, recent discoveries have uncovered critical roles for TREX1 in shaping tumor immunogenicity and modulating antiviral defense through regulation of DNA-sensing pathways. In this review, we summarize current insights into the evolutionary origin, structural mechanisms, and functional repertoire of TREX1 in innate immunity. We further discuss how dysregulation of TREX1 contributes to disease and highlight emerging strategies to therapeutically modulate TREX1 activity in cancer and interferonopathies.
Fecal microbiota transplantation for immune regulation: improving ulcerative colitis and enhancing cancer immunotherapy.
Zhang X, Ishikawa D, Nagahara A
Int Immunol · 2026 Jan · PMID 40592776 · Publisher ↗
The gut microbiota plays an integral role in maintaining health and regulating various host functions, including immune responses. Fecal microbiota transplantation (FMT) has emerged as a promising therapeutic approach to...
The gut microbiota plays an integral role in maintaining health and regulating various host functions, including immune responses. Fecal microbiota transplantation (FMT) has emerged as a promising therapeutic approach to restore gut microbial balance. Although widely recognized for its efficacy in treating ulcerative colitis (UC), FMT is now being investigated as an adjuvant therapy to enhance the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment. This review summarizes the clinical applications of FMT in UC treatment and its potential role in cancer immunotherapy. FMT exhibits varying degrees of efficacy in the treatment of UC, with differences in outcomes attributed to variations in administration methods and donor selection. In cancer therapy, FMT has demonstrated the potential to improve ICI responses, particularly in patients with melanoma. However, its effects on other cancers remain unclear. Although FMT holds promise for UC and cancer immunotherapy, challenges such as inconsistent clinical outcomes and methodological variations persist. Standardized protocols and mechanistic studies are crucial to optimize FMT-based therapeutic strategies, and further research is required to establish its efficacy under diverse clinical conditions.
All-trans retinoic acid suppresses IL-4 and IL-13 production in Th2 cells by modulating the nuclear receptor RARα, and Gfi1.
Biswas B, Hazra S, Nandan S … +3 more , Chattopadhyay S, Mansingh SP, Goswami R
Int Immunol · 2025 Dec · PMID 40592768 · Publisher ↗
All-trans retinoic acid (atRA), the bioactive component of vitamin A, plays a pivotal role in various biological processes. atRA, essential for embryonic development and immune functions, primarily mediates its regulator...
All-trans retinoic acid (atRA), the bioactive component of vitamin A, plays a pivotal role in various biological processes. atRA, essential for embryonic development and immune functions, primarily mediates its regulatory effects by interacting with the nuclear receptor RARα (retinoic acid receptor α). atRA-bound RARα enters the nucleus and forms a heterodimer with RXR (retinoid X receptor). This heterodimer can then interact with various transcription factors to form regulatory complexes that influence gene expression. While the role of atRA in regulating the type 2 immune response has been studied, further exploration into its specific involvement in Th2 cell differentiation is necessary to fully elucidate underlying mechanisms and assess its therapeutic potential. Our study shows that atRA suppressed the Th2 phenotype by downregulating type 2 transcription factors such as Spi1 and cMaf, without altering Gata3 expression. atRA also reduced IL-4 and IL-13 production, while enhancing IL-5 expression, potentially through upregulation of Gfi1. atRA increased the Gfi1 recruitment to the Il4 and Il13 promoters, along with the common enhancer Ecr (evolutionarily conserved region). RARα, which is typically an inducer of Il4 and Il13, was observed to decrease recruitment to these loci in atRA-treated Th2 cells. Comparative gene expression analysis revealed a reduction in inflammatory responses in atRA-treated Th2 cells. Furthermore, these cells exhibited a negative correlation with epigenetic modifications and nuclear receptor activity among other biological processes. Collectively, our findings suggest that atRA can effectively suppress the Th2 phenotype in vitro, through the regulation of key type 2 transcription factors and pathways, indicating its potential therapeutic implications for limiting type 2 immune responses.
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