International Immunology[JOURNAL]
Sun
200 papers
Intra-tumoral delivery of 5'ppp-dsRNA induces a robust antitumor response via RIG-I activation and Bcl-2 gene downregulation in a murine model of prostate cancer.
Ganguly K, Metkari SM, Biswas B … +2 more , Subedi R, Madan T
Int Immunol · 2024 Dec · PMID 39387130 · Publisher ↗
Onco-immunotherapy via blocking checkpoint inhibitors has revolutionized the treatment-landscape of several malignancies, though not in the metastatic castration-resistant prostate cancer (PCa) owing to an immunosuppress...
Onco-immunotherapy via blocking checkpoint inhibitors has revolutionized the treatment-landscape of several malignancies, though not in the metastatic castration-resistant prostate cancer (PCa) owing to an immunosuppressive and poorly immunogenic "cold" tumor microenvironment (TME). Turning up the heat of such a cold TME via triggering innate immunity is now of increasing interest to restore immune-surveillance. Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are cytosolic innate-sensors that can detect exogenous RNAs and induce type-I interferons and other pro-inflammatory signaling. RIG-I activation is suggested to be a valuable addition to the treatment approaches for several cancers. However, the knowledge about RIG-I signaling in PCa remains elusive. The present study evaluated the expression of two important RLRs, RIG-I and melanoma differentiation-associated protein 5 (MDA5), along with their downstream partners, mitochondrial antiviral-signaling protein (MAVS) and ERA G-protein-like 1 (ERAL1), during PCa progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The early stage of PCa revealed a significant increment in the expression of RLRs but not MAVS. However, the advanced stage showed downregulated RLR signaling. Further, the therapeutic implication of 5'ppp-dsRNA, a synthetic RIG-I agonist and Bcl2 gene silencer, has been investigated in vitro and in vivo. Intra-tumoral delivery of 5'ppp-dsRNA regressed tumor growth via triggering tumor cell apoptosis, immunomodulation, and inducing phagocytic "eat me" signals. These findings highlight that, for the first time, RIG-I activation and Bcl-2 silencing with 5'ppp-dsRNA can serve as a potent tumor-suppressor strategy in PCa and has a significant clinical implication in transforming a "cold" TME into an immunogenic "hot" TME of PCa.
An abnormal increase in CD26(-)CD28(-) cytotoxic effector CD4 and CD8 T cell populations in patients with systemic lupus erythematosus.
Hatano R, Nakamura H, Yamamoto A … +13 more , Otsuka H, Itoh T, Hosokawa N, Yu J, Ranjbar S, Hasegawa Y, Sato T, Dang NH, Ohnuma K, Morimoto S, Sekigawa I, Ishii T, Morimoto C
Int Immunol · 2025 Feb · PMID 39383111 · Publisher ↗
CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and the increase of CD26+ T cells in inflamed tissues and peripheral blood has been reported in diverse autoimmune diseases. In contrast, o...
CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and the increase of CD26+ T cells in inflamed tissues and peripheral blood has been reported in diverse autoimmune diseases. In contrast, our group has previously shown that levels of circulating CD26+ T cells are decreased in patients with systemic lupus erythematosus (SLE), although the role of reduced CD26 T cell surface expression in SLE pathology remains to be elucidated. In the present study, we conducted CD26-based T cell subset analyses utilizing peripheral blood mononuclear cells from 57 SLE patients and 31 healthy adult volunteers. We show that the increase in the CD26(-) T cell population reflects the abnormal expansion of CD26(-)CD28(-) cytotoxic subsets of both CD8 T cells and CD4 T cells in SLE patients. Single-cell RNA sequencing analysis of the CD26(-)CD28(-) CD4 and CD8 T cell populations reveals unique characteristics with similarities to natural killer T cells. In addition, the level of CD26(-)CD28(-) T cells is increased in some active-stage SLE patients with renal manifestation. Meanwhile, the effect of prednisolone treatment on these populations varies from patient to patient, with levels of these cytotoxic effector populations still being elevated in some inactive-stage SLE patients. Taken together, our data suggest that analysis of these populations in SLE may be a useful tool to classify this markedly heterogeneous condition.
Senescence-associated T cells in immunosenescence and diseases.
Fukushima Y, Ueno R, Minato N … +1 more , Hattori M
Int Immunol · 2025 Feb · PMID 39320393 · Publisher ↗
Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammat...
Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammation often with autoimmunity, which may underlie the development of diverse disorders with age. Immunosenescent phenotypes are associated with the emergence of unique lymphocyte subpopulations of both T and B lineages. We report that a CD153+ programmed cell death protein 1 (PD-1)+ CD4+ T-cell subpopulation with severely attenuated T-cell receptor (TCR)-responsiveness, termed senescence-associated T (SAT) cells, co-evolve with potentially autoreactive CD30+ B cells, such as spontaneous germinal center B cells and age-associated B cells, in aging mice. SAT cells and CD30+ B cells are reciprocally activated with the aid of the interaction of CD153 with CD30 in trans and with the TCR complex in cis, resulting in the restoration of TCR-mediated proliferation and secretion of abundant pro-inflammatory cytokines in SAT cells and the activation and production of autoantibodies by CD30+ B cells. Besides normal aging, the development of SAT cells coupled with counterpart B cells may be robustly accelerated and accumulated in the relevant tissues of lymphoid or extra-lymphoid organs under chronic inflammatory conditions, including autoimmunity, and may contribute to the pathogenesis and aggravation of the disorders. This review summarizes and discusses recent advances in the understanding of SAT cells in the contexts of immunosenescent phenotypes, as well as autoimmune and chronic inflammatory diseases, and it provides a novel therapeutic clue.
The role of the skin in the atopic march.
Tang X, Li M
Int Immunol · 2024 Oct · PMID 39271155 · Publisher ↗
Atopic diseases, including atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are closely related to inflammatory diseases involving different body sites (i.e. the skin, airway, and digestive t...
Atopic diseases, including atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are closely related to inflammatory diseases involving different body sites (i.e. the skin, airway, and digestive tract) with characteristic features including specific IgE to allergens (so-called "atopy") and Th2 cell-mediated inflammation. It has been recognized that AD often precedes the development of other atopic diseases. The progression from AD during infancy to FA or asthma/AR in later childhood is referred to as the "atopic march" (AM). Clinical, genetic, and experimental studies have provided evidence that allergen sensitization occurring through AD skin could be the origin of the AM. Here, we provide an updated review focusing on the role of the skin in the AM, from genetic mutations and environmental factors associated with epidermal barrier dysfunction in AD and the AM to immunological mechanisms for skin sensitization, particularly recent progress on the function of key cytokines produced by epidermal keratinocytes or by immune cells infiltrating the skin during AD. We also highlight the importance of developing strategies that target AD skin to prevent and attenuate the AM.
Mechanisms and effects of activation of innate immunity by mitochondrial nucleic acids.
Rai P, Fessler MB
Int Immunol · 2025 Feb · PMID 39213393 · Full text
In recent years, a growing number of roles have been identified for mitochondria in innate immunity. One principal mechanism is that the translocation of mitochondrial nucleic acid species from the mitochondrial matrix t...
In recent years, a growing number of roles have been identified for mitochondria in innate immunity. One principal mechanism is that the translocation of mitochondrial nucleic acid species from the mitochondrial matrix to the cytosol and endolysosomal lumen in response to an array of microbial and non-microbial environmental stressors has been found to serve as a second messenger event in the cell signaling of the innate immune response. Thus, mitochondrial DNA and RNA have been shown to access the cytosol through several regulated mechanisms involving remodeling of the mitochondrial inner and outer membranes and to access lysosomes via vesicular transport, thereby activating cytosolic [e.g. cyclic GMP-AMP synthase (cGAS), retinoic acid-inducible gene I (RIG-I)-like receptors], and endolysosomal (Toll-like receptor 7, 9) nucleic acid receptors that induce type I interferons and pro-inflammatory cytokines. In this mini-review, we discuss these molecular mechanisms of mitochondrial nucleic acid mislocalization and their roles in host defense, autoimmunity, and auto-inflammatory disorders. The emergent paradigm is one in which host-derived DNA interestingly serves as a signal amplifier in the innate immune response and also as an alarm signal for disturbances in organellar homeostasis. The apparent vast excess of mitochondria and mitochondrial DNA nucleoids per cell may thus serve to sensitize the cell response to stressors while ensuring an underlying reserve of intact mitochondria to sustain cellular metabolism. An improved understanding of these molecular mechanisms will hopefully afford future opportunities for therapeutic intervention in human disease.
Spatial diversity of in vivo tissue immunity.
Miyamoto Y, Ishii M
Int Immunol · 2024 Dec · PMID 39177484 · Publisher ↗
The immune system exhibits spatial diversity in in vivo tissues. Immune cells are strategically distributed within tissues to maintain the organ integrity. Advanced technologies such as intravital imaging and spatial tra...
The immune system exhibits spatial diversity in in vivo tissues. Immune cells are strategically distributed within tissues to maintain the organ integrity. Advanced technologies such as intravital imaging and spatial transcriptomics have revealed the spatial heterogeneity of immune cell distribution and function within organs such as the liver, kidney, intestine, and lung. In addition, these technologies visualize nutrient and oxygen environments across tissues. Recent spatial analyses have suggested that a functional immune niche is determined by interactions between immune and non-immune cells in an appropriate nutrient and oxygen environment. Understanding the spatial communication between immune cells, environment, and surrounding non-immune cells is crucial for developing strategies to control immune responses and effectively manage inflammatory diseases.
The role of dendritic cells in the instruction of helper T cells in the allergic march.
Kubo M, Harada Y, Sasaki T
Int Immunol · 2024 Oct · PMID 39162776 · Publisher ↗
Allergy is a complex array of diseases influenced by innate and adaptive immunity, genetic polymorphisms, and environmental triggers. Atopic dermatitis is a chronic inflammatory skin disease characterized by barrier defe...
Allergy is a complex array of diseases influenced by innate and adaptive immunity, genetic polymorphisms, and environmental triggers. Atopic dermatitis is a chronic inflammatory skin disease characterized by barrier defects and immune dysregulation, sometimes leading to asthma and food allergies because of the atopic march. During atopic skin inflammation, Langerhans cells and dendritic cells (DCs) in the skin capture and deliver allergen information to local lymph nodes. DCs are essential immune sensors coordinating immune reactions by capturing and presenting antigens to T cells. In the context of allergic responses, DCs play a crucial role in instructing two types of helper T cells-type 2 helper T (Th2) cells and follicular helper T (TFH) cells-in allergic responses and IgE antibody responses. In skin sensitization, the differentiation and function of Th2 cells and TFH cells are influenced by skin-derived factors, including epithelial cytokines, chemokines, and signalling pathways to modify the function of migratory DCs and conventional DCs. In this review, we aim to understand the specific mechanisms involving DCs in allergic responses to provide insights into the pathogenesis of allergic diseases and potential therapeutic strategies.
A splice of life: the discovery, function, and clinical implications of FOXP3 isoforms in autoimmune disease.
Weinstein KN, Domeier PP, Ziegler SF
Int Immunol · 2024 Dec · PMID 39136284 · Full text
Regulatory T cells (Tregs) are a specialized subset of CD4+ T cells essential for the maintenance of immune homeostasis and prevention of autoimmunity. Treg lineage and functions are programmed by the X-chromosome encode...
Regulatory T cells (Tregs) are a specialized subset of CD4+ T cells essential for the maintenance of immune homeostasis and prevention of autoimmunity. Treg lineage and functions are programmed by the X-chromosome encoded transcription factor forkhead box P3 (FOXP3). In humans, multiple FOXP3 isoforms are generated through alternative splicing. A full-length isoform containing all coding exons (FOXP3-FL) and a version lacking the second exon (FOXP3-ΔE2) are the predominant FOXP3 isoforms. Additionally, there are two minor isoforms lacking either exon 7 (FOXP3-ΔE7) and both exons 2 and 7 (FOXP3-ΔE2ΔE7). Although healthy humans express approximately equal levels of the FOXP3-FL and FOXP3-ΔE2 isoforms, sole expression of FOXP3-ΔE2 results in the development of a systemic autoimmune disease that resembles immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. These clinical observations strongly suggest functional defects in suppression by Tregs programmed by the FOXP3-ΔE2 isoform. Work from the past two decades has provided phenotypic and functional evidence of differences between Tregs programmed by the FOXP3-FL, FOXP3-ΔE2, and FOXP3-ΔE7 isoforms. In this review, we discuss the discovery of the FOXP3 isoforms, differences in the phenotype and function of Tregs programmed by different FOXP3 isoforms, and the role that these isoforms are known to play in autoimmunity.
The active form of vitamin D (calcitriol) promotes CXCR5 expression during follicular helper T cell differentiation.
Iwata M, Takada A, Sakamoto R … +2 more , Song SY, Ito E
Int Immunol · 2024 Nov · PMID 39101520 · Full text
Follicular helper T (Tfh) cells promote B cell differentiation and antibody production in the B cell follicles of secondary lymphoid organs. Tfh cells express their signature transcription factor BCL6, interleukin (IL)-2...
Follicular helper T (Tfh) cells promote B cell differentiation and antibody production in the B cell follicles of secondary lymphoid organs. Tfh cells express their signature transcription factor BCL6, interleukin (IL)-21, and surface molecules including inducible T cell costimulator (ICOS), programmed cell death-1 (PD-1), and C-X-C motif chemokine receptor 5 (CXCR5). Migration of Tfh cells to B cell follicles largely depends on the CXCR5 expression induced by interactions with antigen-presenting dendritic cells in the T cell area. How Tfh cells acquire sufficient levels of CXCR5 expression, however, has remained unclear. Using our in vitro culture system to generate CXCR5low Tfh-like cells from naive CD4+ T cells with IL-6 in the absence of other cell types, we found that the active form of vitamin D, calcitriol, markedly enhanced CXCR5 expression after the release from persistent T cell receptor (TCR) stimulation. CH-223191, an aryl hydrocarbon receptor antagonist, further enhanced CXCR5 expression. IL-12 but not IL-4, in place of IL-6, also supported calcitriol to enhance CXCR5 expression even before the release from TCR stimulation, whereas the cell viability sharply decreased after the release. The Tfh-like cells generated with IL-6 and calcitriol exhibited chemotaxis toward C-X-C motif chemokine ligand 13 (CXCL13), expressed IL-21, and helped B cells to produce IgG antibodies in vitro more efficiently than Tfh-like cells generated without added calcitriol. Calcitriol injections into antigen-primed mice increased the proportion of CXCR5+PD-1+CD4+ cells in their lymphoid organs, and enhanced T cell entry into B cell follicles. These results suggest that calcitriol promotes CXCR5 expression in developing Tfh cells and regulates their functional differentiation.
Pathogenesis of IgA nephropathy as a tissue-specific autoimmune disease.
Nihei Y, Kitamura D
Int Immunol · 2024 Dec · PMID 39066568 · Publisher ↗
Glomerulonephritis (GN) is a group of heterogeneous immune-mediated kidney diseases that causes inflammation within the glomerulus. Autoantibodies (auto-Abs) are considered to be central effectors in the pathogenesis of...
Glomerulonephritis (GN) is a group of heterogeneous immune-mediated kidney diseases that causes inflammation within the glomerulus. Autoantibodies (auto-Abs) are considered to be central effectors in the pathogenesis of several types of GN. Immunoglobulin A nephropathy (IgAN) is the most common GN worldwide and is characterized by the deposition of IgA in the glomerular mesangium of the kidneys, which is thought to be mediated by immune complexes containing non-specific IgA. However, we recently reported that IgA auto-Abs specific to mesangial cells (anti-mesangium IgA) were found in the sera of gddY mice, a spontaneous IgAN model, and patients with IgAN. We identified two autoantigens (β2-spectrin and CBX3) that are selectively expressed on the mesangial cell surface and targeted by anti-mesangial IgA. Our findings redefined IgAN as a tissue-specific autoimmune disease. Regarding the mechanisms of production of anti-mesangium IgA, studies using gddY mice have revealed that the production of anti-CBX3 IgA is induced by particular strains of commensal bacteria in the oral cavity, possibly through their molecular mimicry to CBX3. Here, we discuss a new concept of IgAN pathogenesis from the perspective of this disease as autoimmune GN caused by tissue-specific auto-Abs.
CCR2-dependent placental migration of inflammatory monocytes suppresses abnormal pregnancies caused by Toxoplasma gondii infection.
Kamiyama N, Ueno M, Sasaki Y … +9 more , Chalalai T, Sachi N, Ozaka S, Soga Y, Kagoshima Y, Ekronarongchai S, Okamoto M, Yamamoto M, Kobayashi T
Int Immunol · 2024 Nov · PMID 39051675 · Full text
Toxoplasma gondii (T. gondii) is a zoonotic protozoan parasite that causes congenital toxoplasmosis, including fetal death, abortion, stillbirth, morphological abnormalities, and premature birth. Primary T. gondii infect...
Toxoplasma gondii (T. gondii) is a zoonotic protozoan parasite that causes congenital toxoplasmosis, including fetal death, abortion, stillbirth, morphological abnormalities, and premature birth. Primary T. gondii infection in pregnant women results in congenital toxoplasmosis. C-C chemokine receptor (CCR) 2 is reportedly a critical host defense factor against T. gondii infection. However, details of the role of CCR2 in the host immune response to T. gondii in congenital toxoplasmosis remain unclear. Here, we infected pregnant CCR2-deficient mice with T. gondii, resulting in stillbirth, embryonic resorption, fetal morphological abnormalities, and preterm delivery at significantly higher rates than those in pregnant wild-type (WT) mice. Consistent with the severity of abnormal pregnancy, a large area of placental hemorrhage and a large number of T. gondii infections around the hemorrhagic area were observed in the placentas of CCR2-deficient mice. In addition, the accumulation of inflammatory monocytes in the placenta was reduced in CCR2-deficient mice during infection. We further confirmed that the adoptive transfer of inflammatory monocytes collected from WT mice into T. gondii-infected pregnant CCR2-deficient mice effectively suppressed placental damage and abnormal pregnancy. Collectively, CCR2 contributes to pregnancy maintenance by regulating the migration of inflammatory monocytes into the placenta of T. gondii-infected pregnant mice.
The canonical Hippo pathway components modulate the differentiation of lamina propria regulatory T cells and T helper 17-like regulatory T cells in mouse colitis.
Ge L, Xu M, Huang M … +7 more , Liu S, Zhou Z, Xia Z, Dong S, Zhao Q, Zhu R, Zhou F
Int Immunol · 2024 Nov · PMID 38955508 · Publisher ↗
Regulatory T cells (Tregs) ameliorate inflammatory bowel diseases. However, their plasticity is not completely understood. In this study using a mouse colitis model, Tregs and T helper 17 (Th17)-like Tregs were detected...
Regulatory T cells (Tregs) ameliorate inflammatory bowel diseases. However, their plasticity is not completely understood. In this study using a mouse colitis model, Tregs and T helper 17 (Th17)-like Tregs were detected and sorted using flow cytometry, followed by transcriptome sequencing, real-time reverse transcription polymerase chain reaction, and flow cytometry to analyze the mRNA profiles of these cells. Treg plasticity was evaluated by in vitro differentiation assays. The immunosuppressive activities of Tregs and Th17-like Tregs were assessed in an adoptive transfer assay. We found Treg-derived Th17-like Tregs in inflamed colonic lamina propria (LP). LP Th17-like Tregs expressed higher Th17-related cytokines and lower immunosuppressive cytokines compared with LP Tregs. Notably, Tregs expressed higher Yes-associated protein 1 (YAP1) but lower transcriptional coactivator with PDZ-binding motif (TAZ) than Th17-like Tregs. Verteporfin-mediated inhibition of YAP1 activity enhanced Th17-like Treg generation, whereas IBS008739-induced TAZ activation did not affect Th17-like Treg generation. Besides, verteporfin enhanced while IBS008739 suppressed the differentiation of Th17-like Tregs into Th17 cells. Furthermore, YAP1 activated STAT5 signaling in Tregs, whereas YAP1 and TAZ activated STAT3 and STAT5 signaling in Th17-like Tregs. Compared with Tregs, Th17-like Tregs were less efficacious in ameliorating colitis. Therefore, YAP1 suppressed Treg differentiation into Th17-like Tregs. Both YAP1 and TAZ inhibited the differentiation of Th17-like Tregs into Th17 cells. Therefore, YAP1 and TAZ probably maintain the immunosuppressive activities of Tregs and Th17-like Tregs in colitis.
Diverse roles of dendritic cell and regulatory T cell crosstalk in controlling health and disease.
Yamazaki S
Int Immunol · 2024 Nov · PMID 38953561 · Publisher ↗
Dendritic cells (DCs) are specialized antigen-presenting cells for lymphocytes, including regulatory T (Treg) cells, a subset of CD4+ T cells expressing CD25 and Foxp3, a transcription factor. Treg cells maintain immunol...
Dendritic cells (DCs) are specialized antigen-presenting cells for lymphocytes, including regulatory T (Treg) cells, a subset of CD4+ T cells expressing CD25 and Foxp3, a transcription factor. Treg cells maintain immunological self-tolerance in mice and humans, and suppress autoimmunity and other various immune responses such as tumor immunity, transplant rejection, allergy, responses to microbes, and inflammation. Treg-cell proliferation is controlled by antigen-presenting DCs. On the other hand, Treg cells suppress the function of DCs by restraining DC maturation. Therefore, the interaction between DCs and Treg cells, DC-Treg crosstalk, could contribute to controlling health and disease. We recently found that unique DC-Treg crosstalk plays a role in several conditions. First, Treg cells are expanded in ultraviolet B (UVB)-exposed skin by interacting with DCs, and the UVB-expanded Treg cells have a healing function. Second, manipulating DC-Treg crosstalk can induce effective acquired immune responses against severe acute respiratory syndrome coronavirus 2 antigens without adjuvants. Third, Treg cells with a special feature interact with DCs in the tumor microenvironment of human head and neck cancer, which may contribute to the prognosis. Understanding the underlying mechanisms of DC-Treg crosstalk may provide a novel strategy to control health and disease.
New approaches to the control of chronic inflammatory diseases with a focus on the endolysosomal system of immune cells.
Toyama-Sorimachi N
Int Immunol · 2024 Nov · PMID 38946351 · Full text
Chronic inflammation is implicated in many types of diseases, including cardiovascular, neurodegenerative, metabolic, and immune disorders. The search for therapeutic targets to control chronic inflammation often involve...
Chronic inflammation is implicated in many types of diseases, including cardiovascular, neurodegenerative, metabolic, and immune disorders. The search for therapeutic targets to control chronic inflammation often involves narrowing down the various molecules associated with pathology that have been discovered by various omics analyses. Herein, a different approach to identify therapeutic targets against chronic inflammation is proposed and one such target is discussed as an example. In chronically inflamed tissues, a large number of cells receive diverse proinflammatory signals, the intracellular signals are intricately integrated, and complicated intercellular interactions are orchestrated. This review focuses on effectively blocking this chaotic inflammatory signaling network via the endolysosomal system, which acts as a cellular signaling hub. In endolysosomes, the inflammatory signals mediated by pathogen sensors, such as Toll-like receptors, and the signals from nutrient and metabolic pathways are integrally regulated. Disruption of endolysosome signaling results in a strong anti-inflammatory effect by disrupting various signaling pathways, including pathogen sensor-mediated signals, in multiple immune cells. The endolysosome-resident amino acid transporter, solute carrier family 15 member 4 (SLC15A4), which plays an important role in the regulation of endolysosome-mediated signals, is a promising therapeutic target for several inflammatory diseases, including autoimmune diseases. The mechanisms by which SLC15A4 regulates inflammatory responses may provide a proof of concept for the efficacy of therapeutic strategies targeting immune cell endolysosomes.
Synchronized development of thymic eosinophils and thymocytes.
Ota A, Iguchi T, Nitta S … +6 more , Muro R, Mino N, Tsukasaki M, Penninger JM, Nitta T, Takayanagi H
Int Immunol · 2024 Nov · PMID 38916145 · Full text
The thymus is an organ required for T cell development and is also an eosinophil-rich organ; however, the nature and function of thymic eosinophils remain unclear. Here, we characterized the gene expression and different...
The thymus is an organ required for T cell development and is also an eosinophil-rich organ; however, the nature and function of thymic eosinophils remain unclear. Here, we characterized the gene expression and differentiation mechanism of thymic eosinophils in mice. Thymic eosinophils showed a distinct gene expression profile compared with other organ-resident eosinophils. The number of thymic eosinophils was controlled by medullary thymic epithelial cells (mTECs). In Rag-deficient mice, the unique gene expression signature of thymic eosinophils was lost but restored by pre-T cell receptor signalling, which induces CD4+ CD8+ thymocyte differentiation, indicating that T cell differentiation beyond the CD4- CD8- stage is necessary and sufficient for the induction of thymic eosinophils. These results demonstrate that thymic eosinophils are quantitatively and qualitatively regulated by mTECs and developing thymocytes, respectively, suggesting that thymic eosinophils are a distinct, thymus-specific cell subset, induced by interactions with thymic cells.
Supersulphides suppress type-I and type-II interferon responses by blocking JAK/STAT signalling in macrophages.
Li X, Toyomoto T, Zhang T … +5 more , Guo C, Lindahl S, Tsutsuki H, Xian M, Sawa T
Int Immunol · 2024 Nov · PMID 38899915 · Publisher ↗
Interferons (IFNs) are cytokines produced and secreted by immune cells when viruses, tumour cells, and so forth, invade the body. Their biological effects are diverse, including antiviral, cell growth-inhibiting, and ant...
Interferons (IFNs) are cytokines produced and secreted by immune cells when viruses, tumour cells, and so forth, invade the body. Their biological effects are diverse, including antiviral, cell growth-inhibiting, and antitumour effects. The main subclasses of IFNs include type-I (e.g. IFN-α and IFN-β) and type-II (IFN-γ), which activate intracellular signals by binding to type-I and type-II IFN receptors, respectively. We have previously shown that when macrophages are treated with supersulphide donors, which have polysulphide structures in which three or more sulphur atoms are linked within the molecules, IFN-β-induced cellular responses, including signal transducer and activator of transcription 1 (STAT1) phosphorylation and inducible nitric oxide synthase (iNOS) expression, were strongly suppressed. However, the subfamily specificity of the suppression of IFN signals by supersulphides and the mechanism of this suppression are unknown. This study demonstrated that supersulphide donor N-acetyl-L-cysteine tetrasulphide (NAC-S2) can inhibit IFN signalling in macrophages stimulated not only with IFN-α/β but also with IFN-γ. Our data suggest that NAC-S2 blocks phosphorylation of Janus kinases (JAKs), thereby contributing to the inhibition of phosphorylation of STAT1. Under the current experimental conditions, the hydrogen sulphide (H2S) donor NaHS failed to inhibit IFN signalling. Similar to NAC-S2, the carbohydrate-based supersulphide donor thioglucose tetrasulphide (TGS4) was capable of strongly inhibiting tumour necrosis factor-α production, iNOS expression, and nitric oxide production from macrophages stimulated with lipopolysaccharide. Further understanding of the molecular mechanisms by which supersulphide donors exhibit their inhibitory actions towards JAK/STAT signalling is a necessary basis for the development of supersulphide-based therapeutic strategy against autoimmune disorders with dysregulated IFN signalling.
Regulation of memory CD4+ T-cell generation by intrinsic and extrinsic IL-27 signaling during malaria infection.
Tsogtsaikhan S, Inoue SI, Bayarsaikhan G … +7 more , Macalinao ML, Kimura D, Miyakoda M, Yamamoto M, Hara H, Yoshida H, Yui K
Int Immunol · 2024 Nov · PMID 38895753 · Publisher ↗
The generation and maintenance of memory T cells are regulated by various factors, including cytokines. Previous studies have shown that IL-27 is produced during the early acute phase of Plasmodium chabaudi chabaudi AS (...
The generation and maintenance of memory T cells are regulated by various factors, including cytokines. Previous studies have shown that IL-27 is produced during the early acute phase of Plasmodium chabaudi chabaudi AS (Pcc) infection and inhibits the development of Th1-type memory CD4+ T cells. However, whether IL-27 acts directly on its receptor on Plasmodium-specific CD4+ T cells or indirectly via its receptor on other immune cells remains unclear. We aimed to determine the role of IL-27 receptor signaling in different immune cell types in regulating the generation and phenotype of memory CD4+ T cells during Plasmodium infection. We utilized Plasmodium-specific T-cell antigen receptor (TCR) transgenic mice, PbT-II, and Il27rα-/- mice to assess the direct and indirect effects of IL-27 signaling on memory CD4+ T-cell generation. Mice were transferred with PbT-II or Il27rα-/- PbT-II cells and infected with Pcc. Conditional knockout mice lacking the IL-27 receptor in T cells or dendritic cells were employed to discern the specific immune cell types involved in IL-27 receptor signaling. High levels of memory in PbT-II cells with Th1-shift occurred only when both PbT-II and host cells lacked the IL-27 receptor, suggesting the predominant inhibitory role of IL-27 signaling in both cell types. Furthermore, IL-27 receptor signaling in T cells limited the number of memory CD4+ T cells, while signaling in both T and dendritic cells contributed to the Th1 dominance of memory CD4+ T cells. These findings underscore the complex cytokine signaling network regulating memory CD4+ T cells during Plasmodium infection.
The skin barrier and microbiome in infantile atopic dermatitis development: can skincare prevent onset?
Ito T, Nakamura Y
Int Immunol · 2024 Oct · PMID 38887075 · Publisher ↗
Atopic dermatitis (AD), a prevalent Th2-dominant skin disease, involves complex genetic and environmental factors, including mutations in the Filaggrin gene and dysbiosis of skin microbiota characterized by an increased...
Atopic dermatitis (AD), a prevalent Th2-dominant skin disease, involves complex genetic and environmental factors, including mutations in the Filaggrin gene and dysbiosis of skin microbiota characterized by an increased abundance of Staphylococcus aureus. Our recent findings emphasize the pivotal role of the skin barrier's integrity and microbial composition in infantile AD and allergic diseases. Early skin dysbiosis predisposes infants to AD, suggesting targeted skincare practices as a preventive strategy. The effects of skincare interventions, particularly the application of moisturizers with the appropriate molar concentration of ceramides, cholesterol, and fatty acids, play a crucial role in restoring the skin barrier. Notably, our study revealed that appropriate skincare can reduce Streptococcus abundance while supporting Cutibacterium acnes presence, thus directly linking skincare practices to microbial modulation in neonatal skin. Despite the mixed outcomes of previous Randomized Controlled Trials on the efficacy of moisturizers in AD prevention, our research points to the potential of skincare intervention as a primary preventive method against AD by minimizing the impact of genetic and environmental factors. Furthermore, our research supports the notion that early aggressive management of eczema may reduce the incidence of food allergies, highlighting the necessity for multifaceted prevention strategies that address both the skin barrier and immune sensitization. By focusing on repairing the skin barrier and adjusting the skin's microbiome from birth, we propose a novel perspective on preventing infantile AD and allergic diseases, opening new avenues for future studies, and practices in allergy prevention.
The tryptophan metabolic pathway of the microbiome and host cells in health and disease.
Miyamoto K, Sujino T, Kanai T
Int Immunol · 2024 Nov · PMID 38869080 · Full text
The intricate and dynamic tryptophan (Trp) metabolic pathway in both the microbiome and host cells highlights its profound implications for health and disease. This pathway involves complex interactions between host cell...
The intricate and dynamic tryptophan (Trp) metabolic pathway in both the microbiome and host cells highlights its profound implications for health and disease. This pathway involves complex interactions between host cellular and bacteria processes, producing bioactive compounds such as 5-hydroxytryptamine (5-HT) and kynurenine derivatives. Immune responses to Trp metabolites through specific receptors have been explored, highlighting the role of the aryl hydrocarbon receptor in inflammation modulation. Dysregulation of this pathway is implicated in various diseases, such as Alzheimer's and Parkinson's diseases, mood disorders, neuronal diseases, autoimmune diseases such as multiple sclerosis (MS), and cancer. In this article, we describe the impact of the 5-HT, Trp, indole, and Trp metabolites on health and disease. Furthermore, we review the impact of microbiome-derived Trp metabolites that affect immune responses and contribute to maintaining homeostasis, especially in an experimental autoimmune encephalitis model of MS.
γδ intraepithelial lymphocytes acquire the ability to produce IFN-γ in a different time course than αβ intraepithelial lymphocytes.
Tani-Ichi S, Ikuta K
Int Immunol · 2024 Nov · PMID 38835285 · Publisher ↗
An age-dependent increase in interferon (IFN)-γ expression by intestinal intraepithelial lymphocytes (IELs) contributes to the acquisition of resistance to infection by pathogens. However, how IELs acquire the ability to...
An age-dependent increase in interferon (IFN)-γ expression by intestinal intraepithelial lymphocytes (IELs) contributes to the acquisition of resistance to infection by pathogens. However, how IELs acquire the ability to produce IFN-γ remains to be elucidated. Here, we report that IELs in the small intestine acquire the ability to rapidly produce IFN-γ at two distinct life stages. TCRαβ+ IELs (αβIELs) started producing IFN-γ at 4 weeks of age, within 1 week after weaning. In contrast, TCRγδ+ IELs (γδIELs) started producing IFN-γ at 7 weeks of age. In mice lacking Eγ4, an enhancer of the TCRγ locus (Eγ4-/- mice), Thy-1+ Vγ5+ γδIELs, a major subpopulation of γδIELs, were specifically reduced and their ability to produce IFN-γ was severely impaired, whereas Vγ2+ γδIELs normally produced IFN-γ. In Eγ4-/- mice, TCR expression levels were reduced in Vγ5+ γδIEL precursors in the thymus but unchanged in the Vγ5+ IELs. Nevertheless, TCR responsiveness in Vγ5+ γδIELs was impaired in Eγ4-/- mice, suggesting that the TCR signal received in the thymus may determine TCR responsiveness and the ability to produce IFN-γ in the gut. These results suggest that αβIELs and γδIELs start producing IFN-γ at different life stages and that the ability of Vγ5+ γδIELs to produce IFN-γ in the gut may be predetermined by TCR signalling in IEL precursors in the thymus.
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