41 results on '"Kimura MY"'
Search Results
2. Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients.
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Aoki A, Iwamura C, Kiuchi M, Tsuji K, Sasaki A, Hishiya T, Hirasawa R, Kokubo K, Kuriyama S, Onodera A, Shimada T, Nagaoka T, Ishikawa S, Kojima A, Mito H, Hase R, Kasahara Y, Kuriyama N, Nakamura S, Urushibara T, Kaneda S, Sakao S, Nishida O, Takahashi K, Kimura MY, Motohashi S, Igari H, Ikehara Y, Nakajima H, Suzuki T, Hanaoka H, Nakada TA, Kikuchi T, Nakayama T, Yokote K, and Hirahara K
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- Female, Humans, Male, Dendritic Cells immunology, SARS-CoV-2 immunology, Severity of Illness Index, Signal Transduction immunology, Autoantibodies immunology, Autoantibodies blood, COVID-19 immunology, Interferon Type I immunology, Interferon Type I metabolism, Myeloid Cells immunology
- Abstract
Purpose: Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs., Methods: We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs., Results: Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor., Conclusion: Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity., (© 2024. The Author(s).)
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- 2024
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3. Exploring the Role of Platelets in Virus-Induced Inflammatory Demyelinating Disease and Myocarditis.
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Ahmad I, Omura S, Sato F, Park AM, Khadka S, Gavins FNE, Tanaka H, Kimura MY, and Tsunoda I
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- Humans, Mice, Animals, Central Nervous System metabolism, Histocompatibility Antigens Class I metabolism, Chronic Disease, Myocarditis etiology, Myocarditis metabolism, Multiple Sclerosis metabolism
- Abstract
Theiler's murine encephalomyelitis virus (TMEV) infection has been used as a mouse model for two virus-induced organ-specific immune-mediated diseases. TMEV-induced demyelinating disease (TMEV-IDD) in the central nervous system (CNS) is a chronic inflammatory disease with viral persistence and an animal model of multiple sclerosis (MS) in humans. TMEV infection can also cause acute myocarditis with viral replication and immune cell infiltration in the heart, leading to cardiac fibrosis. Since platelets have been reported to modulate immune responses, we aimed to determine the role of platelets in TMEV infection. In transcriptome analyses of platelets, distinct sets of immune-related genes, including major histocompatibility complex (MHC) class I, were up- or downregulated in TMEV-infected mice at different time points. We depleted platelets from TMEV-infected mice by injecting them with platelet-specific antibodies. The platelet-depleted mice had significantly fewer viral antigen-positive cells in the CNS. Platelet depletion reduced the severities of TMEV-IDD and myocarditis, although the pathology scores did not reach statistical significance. Immunologically, the platelet-depleted mice had an increase in interferon (IFN)-γ production with a higher anti-TMEV IgG2a/IgG1 ratio. Thus, platelets may play roles in TMEV infection, such as gene expression, viral clearance, and anti-viral antibody isotype responses.
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- 2024
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4. ACC1-mediated fatty acid biosynthesis intrinsically controls thymic iNKT cell development.
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Kanno T, Miyako K, Endo T, Yokoyama S, Asou HK, Yamada K, Ohara O, Nakayama T, Kimura MY, and Endo Y
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- Animals, Mice, Adipogenesis, Cell Differentiation, Fatty Acids metabolism, Acetyl-CoA Carboxylase genetics, Acetyl-CoA Carboxylase metabolism, Natural Killer T-Cells, Thymus Gland cytology, Thymus Gland metabolism
- Abstract
To meet the energetic requirements associated with activation, proliferation, and survival, T cells switch their metabolic signatures from energetically quiescent to activated. However, little is known about the role of metabolic pathway controlling the development of invariant natural killer T (iNKT) cells. In the present study, we found that acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme for the fatty acid biosynthesis pathway, plays an essential role in the development of iNKT cells in the thymus. Mice lacking T-cell specific ACC1 showed a reduced number of iNKT cells with an increased proportion of iNKT cells at immature stages 0 and 1. Furthermore, mixed bone marrow (BM) chimera experiments revealed that T-cell intrinsic ACC1 expression was selectively important for the development of thymic iNKT cells, especially for the differentiation of the NKT1 cell subset. Our single-cell RNA-sequencing (scRNA-seq) data and functional analysis demonstrated that ACC1 is responsible for survival of developing iNKT cells. Thus, these findings highlighted a novel role of ACC1 in controlling thymic iNKT cell development mediated by the control of cell survival., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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5. CD69 Imposes Tumor-Specific CD8+ T-cell Fate in Tumor-Draining Lymph Nodes.
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Koyama-Nasu R, Kimura MY, Kiuchi M, Aoki A, Wang Y, Mita Y, Hasegawa I, Endo Y, Onodera A, Hirahara K, Motohashi S, and Nakayama T
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- Humans, Cell Differentiation, Lymph Nodes, CD8-Positive T-Lymphocytes, Neoplasms therapy, Neoplasms pathology
- Abstract
Tumor-specific CD8+ T cells play a pivotal role in antitumor immunity and are a key target of immunotherapeutic approaches. Intratumoral CD8+ T cells are heterogeneous; Tcf1+ stemlike CD8+ T cells give rise to their cytotoxic progeny-Tim-3+ terminally differentiated CD8+ T cells. However, where and how this differentiation process occurs has not been elucidated. We herein show that terminally differentiated CD8+ T cells can be generated within tumor-draining lymph nodes (TDLN) and that CD69 expression on tumor-specific CD8+ T cells controls its differentiation process through regulating the expression of the transcription factor TOX. In TDLNs, CD69 deficiency diminished TOX expression in tumor-specific CD8+ T cells, and consequently promoted generation of functional terminally differentiated CD8+ T cells. Anti-CD69 administration promoted the generation of terminally differentiated CD8+ T cells, and the combined use of anti-CD69 and anti-programmed cell death protein 1 (PD-1) showed an efficient antitumor effect. Thus, CD69 is an attractive target for cancer immunotherapy that synergizes with immune checkpoint blockade., (©2023 American Association for Cancer Research.)
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- 2023
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6. Pathogenic helper T cells as the novel therapeutic targets for immune-mediated intractable diseases.
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Onodera A, Kokubo K, Okano M, Onoue M, Kiuchi M, Iwamura C, Iinuma T, Kimura MY, Ebihara N, Hanazawa T, Nakayama T, and Hirahara K
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- Humans, Cytokines, Interleukin-5 therapeutic use, Th2 Cells, Hypersensitivity drug therapy, Dermatitis, Atopic
- Abstract
Allergic diseases arise from a complex interplay between immune system and environmental factors. A link between the pathogenesis of allergic diseases and type 2 immune responses has become evident, with conventional and pathogenic type 2 helper T (Th2) cells involved in both. Recently, there has been a significant development in therapeutic agents for allergic diseases: IL-5 and IL-5 receptor antagonists, Janus kinase (JAK) inhibitors, and sublingual immunotherapy (SLIT). Mepolizumab, an IL-5, and Benralizumab, an IL-5 receptor antagonist, modulate eosinophilic inflammation mediated by IL-5-producing Th2 cells. Delgocitinib shows that JAK-associated signaling is essential for the inflammatory reaction in atopic dermatitis, one of the common allergic diseases. SLIT has a significant effect on allergic rhinitis by reducing pathogenic Th2 cell numbers. More recently, novel molecules that are involved in pathogenic Th2 cell-mediated allergic diseases have been identified. These include calcitonin gene-related peptide (CGRP), reactive oxygen species (ROS) scavenging machinery regulated by the Txnip-Nrf2-Blvrb axis, and myosin light chain 9 (Myl9), which interacts with CD69. This review provides an updated view of the recent research on treatment of allergic diseases and their cause: conventional and pathogenic Th2 cells., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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7. Increased Myosin light chain 9 expression during Kawasaki disease vasculitis.
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Kobayashi H, Kimura MY, Hasegawa I, Suganuma E, Ikehara Y, Azuma K, Ito T, Ebata R, Kurashima Y, Kawasaki Y, Shiko Y, Saito N, Iwase H, Lee Y, Noval Rivas M, Arditi M, Zuka M, Hamada H, and Nakayama T
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- Animals, Mice, Myosin Light Chains metabolism, Immunoglobulins, Intravenous therapeutic use, Inflammation complications, Mucocutaneous Lymph Node Syndrome complications, Vasculitis complications
- Abstract
Introduction: Kawasaki disease (KD) is an acute systemic vasculitis that predominantly afflicts children. KD development is known to be associated with an aberrant immune response and abnormal platelet activation, however its etiology is still largely unknown. Myosin light chain 9 (Myl9) is known to regulate cellular contractility of both non-muscle and smooth muscle cells, and can be released from platelets, whereas any relations of Myl9 expression to KD vasculitis have not been examined., Methods: Plasma Myl9 concentrations in KD patients and children with febrile illness were measured and associated with KD clinical course and prognosis. Myl9 release from platelets in KD patients was also evaluated in vitro. Myl9 expression was determined in coronary arteries from Lactobacillus casei cell wall extract (LCWE)-injected mice that develop experimental KD vasculitis, as well as in cardiac tissues obtained at autopsy from KD patients., Results and Discussion: Plasma Myl9 levels were significantly higher in KD patients during the acute phase compared with healthy controls or patients with other febrile illnesses, declined following IVIG therapy in IVIG-responders but not in non-responders. In vitro, platelets from KD patients released Myl9 independently of thrombin stimulation. In the LCWE-injected mice, Myl9 was detected in cardiac tissue at an early stage before inflammatory cell infiltration was observed. In tissues obtained at autopsy from KD patients, the highest Myl9 expression was observed in thrombi during the acute phase and in the intima and adventitia of coronary arteries during the chronic phase. Thus, our studies show that Myl9 expression is significantly increased during KD vasculitis and that Myl9 levels may be a useful biomarker to estimate inflammation and IVIG responsiveness to KD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kobayashi, Kimura, Hasegawa, Suganuma, Ikehara, Azuma, Ito, Ebata, Kurashima, Kawasaki, Shiko, Saito, Iwase, Lee, Noval Rivas, Arditi, Zuka, Hamada and Nakayama.)
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- 2023
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8. The cellular and molecular basis of CD69 function in anti-tumor immunity.
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Koyama-Nasu R, Wang Y, Hasegawa I, Endo Y, Nakayama T, and Kimura MY
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- Antibodies, Monoclonal therapeutic use, CD8-Positive T-Lymphocytes metabolism, Immunotherapy, Sphingosine-1-Phosphate Receptors, Tumor Microenvironment, Immune Checkpoint Inhibitors, Myosin Light Chains metabolism
- Abstract
Cancer immunotherapy utilizes our immune system to attack cancer cells and is an extremely promising strategy for cancer treatment. Although immune-checkpoint blockade, such as anti-PD-1 (programmed cell death 1) antibody, has demonstrated significant enhancement of anti-tumor immunity and has induced notable clinical outcomes, its response rates remain low, and adverse effects are always a matter of concern; therefore, new targets for cancer immunotherapy are always desired. In this situation, new concepts are needed to fuel the investigation of new target molecules for cancer immunotherapy. We propose that CD69 is one such target molecule. CD69 is known to be an activation marker of leukocytes and is also considered a crucial regulator of various immune responses through its interacting proteins. CD69 promotes T-cell retention in lymphoid tissues via sphingosine-1-phosphate receptor 1 (S1P1) internalization and also plays roles in the pathogenesis of inflammatory disorders through interacting with its functional ligands Myl9/12 (myosin light chains 9, 12a and 12b). In anti-tumor immunity, CD69 is known to be expressed on T cells in the tumor microenvironment (TME) and tumor-draining lymph nodes (TDLNs). We revealed that CD69 negatively regulates the effector function of intratumoral T cells and importantly controls the 'exhaustion' of CD8 T cells. In addition, we and others showed that either CD69 deficiency or the administration of anti-CD69 monoclonal antibody enhances anti-tumor immunity. Thus, CD69 is an attractive target for cancer immunotherapy., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
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9. Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2-induced lung exudative vasculitis and predicts COVID-19 severity.
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Iwamura C, Hirahara K, Kiuchi M, Ikehara S, Azuma K, Shimada T, Kuriyama S, Ohki S, Yamamoto E, Inaba Y, Shiko Y, Aoki A, Kokubo K, Hirasawa R, Hishiya T, Tsuji K, Nagaoka T, Ishikawa S, Kojima A, Mito H, Hase R, Kasahara Y, Kuriyama N, Tsukamoto T, Nakamura S, Urushibara T, Kaneda S, Sakao S, Tobiume M, Suzuki Y, Tsujiwaki M, Kubo T, Hasegawa T, Nakase H, Nishida O, Takahashi K, Baba K, Iizumi Y, Okazaki T, Kimura MY, Yoshino I, Igari H, Nakajima H, Suzuki T, Hanaoka H, Nakada TA, Ikehara Y, Yokote K, and Nakayama T
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- Humans, Leukocytes, Mononuclear, RNA-Seq, Single-Cell Analysis, Spectrometry, X-Ray Emission, COVID-19 blood, COVID-19 complications, COVID-19 pathology, Lung blood supply, Lung metabolism, Lung pathology, Lung virology, Myosin Light Chains blood, SARS-CoV-2 isolation & purification, Severity of Illness Index, Thromboinflammation pathology, Thromboinflammation virology, Vasculitis pathology, Vasculitis virology
- Abstract
The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.
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- 2022
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10. Clinical and Histological Effects of Partial Blood Flow Impairment in Vascularized Lymph Node Transfer.
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Akita S, Ikehara Y, Arai M, Tokumoto H, Yamaji Y, Azuma K, Kubota Y, Haneishi H, Kimura MY, and Mitsukawa N
- Abstract
Regarding vascularized lymph node transfer (VLNT) for lymphedema, partial blood flow impairment in transferred lymph node (LN) flaps may adversely affect the therapeutic results. We investigated the clinical and histological effects of partial blood flow impairment in LN flaps. In upper extremity lymphedema cases, based on ultrasonographic examination at 2 weeks after VLNT, we compared the treatment results depending on whether the postoperative blood flow in transferred LNs was good (Group G) or poor (Group P). Novel partial ischemia and congestion of LN flap mouse models were developed to determine their histological features. In 42 cases, significant differences were observed between Group G ( n = 37) and Group P ( n = 5) based on the amount of volume reduction (136.7 ± 91.7 mL and 55.4 ± 60.4 mL, respectively; p = 0.04) and lymph flow recanalization rate in indocyanine green fluorescent lymphography (67.6% and 0%, respectively; p = 0.0007). In mouse models, thrombi formation in the marginal sinus and numerous Myl9/12-positive immunocompetent cells in follicles were observed in congested LNs. Blood flow maintenance in the transferred LNs is an essential factor influencing the therapeutic effect of VLNT. Postoperatively, surgeons should closely monitor blood flow in the transferred LNs, particularly in cases of congestion.
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- 2022
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11. CD4+ T cells in inflammatory diseases: pathogenic T-helper cells and the CD69-Myl9 system.
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Nakayama T, Hirahara K, Kimura MY, Iwamura C, Kiuchi M, Kokubo K, Onodera A, Hashimoto K, and Motohashi S
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- Animals, Humans, Antigens, CD immunology, Antigens, Differentiation, T-Lymphocyte immunology, CD4-Positive T-Lymphocytes immunology, Inflammation immunology, Lectins, C-Type immunology, Myosin Light Chains immunology, T-Lymphocytes, Regulatory immunology
- Abstract
CD4+ T cells not only direct immune responses against infectious micro-organisms but are also involved in the pathogenesis of inflammatory diseases. In the last two to three decades, various researchers have identified and characterized several functional CD4+ T-cell subsets, including T-helper 1 (Th1), Th2, Th9 and Th17 cells and regulatory T (Treg) cells. In this mini-review, we introduce the concept of pathogenic Th cells that induce inflammatory diseases with a model of disease induction by a population of pathogenic Th cells: the 'pathogenic Th population disease-induction model'. We will focus on Th2 cells that induce allergic airway inflammation-pathogenic Th2 cells (Tpath2 cells)-and discuss the nature of Tpath2 cells that shape the pathology of chronic inflammatory diseases. Various Tpath2-cell subsets have been identified and their unique features are summarized in mouse and human systems. Second, we will discuss how Th cells migrate and are maintained in chronic inflammatory lesions. We propose a model known as the 'CD69-Myl9 system'. CD69 is a cell surface molecule expressed on activated T cells and interaction with its ligand myosin light chain 9 (Myl9) is required for the induction of inflammatory diseases. Myl9 molecules in the small vessels of inflamed lungs may play a crucial role in the migration of activated T cells into inflammatory lesions. Emerging evidence may provide new insight into the pathogenesis of chronic inflammatory diseases and contribute to the development of new therapeutic strategies for intractable inflammatory disorders., (© The Japanese Society for Immunology. 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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12. IFNγ suppresses the expression of GFI1 and thereby inhibits Th2 cell proliferation.
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Sarkar MH, Yagi R, Endo Y, Koyama-Nasu R, Wang Y, Hasegawa I, Ito T, Junttila IS, Zhu J, Kimura MY, and Nakayama T
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- Animals, Cell Cycle, Cell Proliferation, Cells, Cultured, Down-Regulation, Gene Deletion, Mice, Mice, Inbred C57BL, Th2 Cells immunology, Th2 Cells metabolism, DNA-Binding Proteins genetics, Interferon-gamma immunology, Th2 Cells cytology, Transcription Factors genetics
- Abstract
While IFNγ is a well-known cytokine that actively promotes the type I immune response, it is also known to suppress the type II response by inhibiting the differentiation and proliferation of Th2 cells. However, the mechanism by which IFNγ suppresses Th2 cell proliferation is still not fully understood. We found that IFNγ decreases the expression of growth factor independent-1 transcriptional repressor (GFI1) in Th2 cells, resulting in the inhibition of Th2 cell proliferation. The deletion of the Gfi1 gene in Th2 cells results in the failure of their proliferation, accompanied by an impaired cell cycle progression. In contrast, the enforced expression of GFI1 restores the defective Th2 cell proliferation, even in the presence of IFNγ. These results demonstrate that GFI1 is a key molecule in the IFNγ-mediated inhibition of Th2 cell proliferation., Competing Interests: The authors declare no conflicts of interest in association with the present study.
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- 2021
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13. Myosin Light Chain 9/12 Regulates the Pathogenesis of Inflammatory Bowel Disease.
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Yokoyama M, Kimura MY, Ito T, Hayashizaki K, Endo Y, Wang Y, Yagi R, Nakagawa T, Kato N, Matsubara H, and Nakayama T
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- Adult, Aged, Animals, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Biomarkers, Case-Control Studies, Diagnosis, Differential, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression, Humans, Immunohistochemistry, Inflammatory Bowel Diseases diagnosis, Inflammatory Bowel Diseases drug therapy, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Male, Mice, Middle Aged, Molecular Targeted Therapy, Myosin Light Chains antagonists & inhibitors, Myosin Light Chains metabolism, Disease Susceptibility, Inflammatory Bowel Diseases etiology, Inflammatory Bowel Diseases metabolism, Myosin Light Chains genetics
- Abstract
The numbers of patients with inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), have been increasing over time, worldwide; however, the pathogenesis of IBD is multifactorial and has not been fully understood. Myosin light chain 9 and 12a and 12b (Myl9/12) are known as ligands of the CD69 molecule. They create "Myl9 nets" that are often detected in inflamed site, which play a crucial role in regulating the recruitment and retention of CD69-expressing effector cells in inflamed tissues. We demonstrated the strong expression of Myl9/12 in the inflamed gut of IBD patients and mice with DSS-induced colitis. The administration of anti-Myl9/12 Ab to mice with DSS-induced colitis ameliorated the inflammation and prolonged their survival. The plasma Myl9 levels in the patients with active UC and CD were significantly higher than those in patients with disease remission, and may depict the disease severity of IBD patients, especially those with UC. Thus, our results indicate that Myl9/12 are involved in the pathogenesis of IBD, and are likely to be a new therapeutic target for patients suffering from IBD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yokoyama, Kimura, Ito, Hayashizaki, Endo, Wang, Yagi, Nakagawa, Kato, Matsubara and Nakayama.)
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- 2021
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14. Essential Role for CD30-Transglutaminase 2 Axis in Memory Th1 and Th17 Cell Generation.
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Suzuki AS, Yagi R, Kimura MY, Iwamura C, Shinoda K, Onodera A, Hirahara K, Tumes DJ, Koyama-Nasu R, Iismaa SE, Graham RM, Motohashi S, and Nakayama T
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- Adoptive Transfer, Animals, Cell Differentiation immunology, Immunophenotyping, Mice, Mice, Transgenic, Protein Glutamine gamma Glutamyltransferase 2, Signal Transduction, Th1 Cells cytology, Th17 Cells cytology, GTP-Binding Proteins metabolism, Immunologic Memory, Ki-1 Antigen metabolism, Th1 Cells immunology, Th1 Cells metabolism, Th17 Cells immunology, Th17 Cells metabolism, Transglutaminases metabolism
- Abstract
Memory helper T (Th) cells are crucial for secondary immune responses against infectious microorganisms but also drive the pathogenesis of chronic inflammatory diseases. Therefore, it is of fundamental importance to understand how memory T cells are generated. However, the molecular mechanisms governing memory Th cell generation remain incompletely understood. Here, we identified CD30 as a molecule heterogeneously expressed on effector Th1 and Th17 cells, and CD30
hi effector Th1 and Th17 cells preferentially generated memory Th1 and Th17 cells. We found that CD30 mediated signal induced Transglutaminase-2 (TG2) expression, and that the TG2 expression in effector Th cells is essential for memory Th cell generation. In fact, Cd30 -deficiency resulted in the impaired generation of memory Th1 and Th17 cells, which can be rescued by overexpression of TG2. Furthermore, transglutaminase-2 ( Tgm2 )-deficient CD4 T cells failed to become memory Th cells. As a result, T cells from Tgm2 -deficient mice displayed impaired antigen-specific antibody production and attenuated Th17-mediated allergic responses. Our data indicate that CD30-induced TG2 expression in effector Th cells is essential for the generation of memory Th1 and Th17 cells, and that CD30 can be a marker for precursors of memory Th1 and Th17 cells., (Copyright © 2020 Suzuki, Yagi, Kimura, Iwamura, Shinoda, Onodera, Hirahara, Tumes, Koyama-Nasu, Iismaa, Graham, Motohashi and Nakayama.)- Published
- 2020
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15. Activated invariant natural killer T cells directly recognize leukemia cells in a CD1d-independent manner.
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Aoki T, Takami M, Takatani T, Motoyoshi K, Ishii A, Hara A, Toyoda T, Okada R, Hino M, Koyama-Nasu R, Kiuchi M, Hirahara K, Kimura MY, Nakayama T, Shimojo N, and Motohashi S
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- Animals, Antigens, CD1d genetics, Biomarkers, Cell Degranulation, Cell Line, Tumor, Costimulatory and Inhibitory T-Cell Receptors metabolism, Cytokines metabolism, Cytotoxicity, Immunologic, Disease Models, Animal, Female, Gene Editing, Heterografts, Humans, Immunophenotyping, Leukemia genetics, Leukemia pathology, Lymphocyte Activation genetics, Mice, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Receptors, Natural Cytotoxicity Triggering metabolism, Antigens, CD1d metabolism, Leukemia immunology, Leukemia metabolism, Lymphocyte Activation immunology, Natural Killer T-Cells immunology, Natural Killer T-Cells metabolism
- Abstract
Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of Vα24 and Vβ11 in humans. iNKT cells specifically recognize glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d. iNKT cells show direct cytotoxicity toward CD1d-positive tumor cells, especially when CD1d presents glycolipid antigens. However, iNKT cell recognition of CD1d-negative tumor cells is unknown, and direct cytotoxicity of iNKT cells toward CD1d-negative tumor cells remains controversial. Here, we demonstrate that activated iNKT cells recognize leukemia cells in a CD1d-independent manner, however still in a TCR-mediated way. iNKT cells degranulated and released Th1 cytokines toward CD1d-negative leukemia cells (K562, HL-60, REH) as well as αGalCer-loaded CD1d-positive Jurkat cells. The CD1d-independent cytotoxicity was enhanced by natural killer cell-activating receptors such as NKG2D, 2B4, DNAM-1, LFA-1 and CD2, but iNKT cells did not depend on these receptors for the recognition of CD1d-negative leukemia cells. In contrast, TCR was essential for CD1d-independent recognition and cytotoxicity. iNKT cells degranulated toward patient-derived leukemia cells independently of CD1d expression. iNKT cells targeted myeloid malignancies more than acute lymphoblastic leukemia. These findings reveal a novel anti-tumor mechanism of iNKT cells in targeting CD1d-negative tumor cells and indicate the potential of iNKT cells for clinical application to treat leukemia independently of CD1d., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
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- 2020
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16. Differentiation of Pathogenic Th17 Cells Is Negatively Regulated by Let-7 MicroRNAs in a Mouse Model of Multiple Sclerosis.
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Angelou CC, Wells AC, Vijayaraghavan J, Dougan CE, Lawlor R, Iverson E, Lazarevic V, Kimura MY, Peyton SR, Minter LM, Osborne BA, Pobezinskaya EL, and Pobezinsky LA
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cell Differentiation immunology, Cytokines metabolism, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Gene Expression Regulation, Immunophenotyping, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Mice, Multiple Sclerosis pathology, RNA Interference, Th17 Cells cytology, Disease Susceptibility, MicroRNAs genetics, Multiple Sclerosis etiology, Multiple Sclerosis metabolism, Th17 Cells immunology, Th17 Cells metabolism
- Abstract
Multiple sclerosis (MS) is a disabling demyelinating autoimmune disorder of the central nervous system (CNS) which is driven by IL-23- and IL-1β-induced autoreactive Th17 cells that traffic to the CNS and secrete proinflammatory cytokines. Th17 pathogenicity in MS has been correlated with the dysregulation of microRNA (miRNA) expression, and specific miRNAs have been shown to promote the pathogenic Th17 phenotype. In the present study, we demonstrate, using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), that let-7 miRNAs confer protection against EAE by negatively regulating the proliferation, differentiation and chemokine-mediated migration of pathogenic Th17 cells to the CNS. Specifically, we found that let-7 miRNAs may directly target the cytokine receptors Il1r1 and Il23r , as well as the chemokine receptors Ccr2 and Ccr5 . Therefore, our results identify a novel regulatory role for let-7 miRNAs in pathogenic Th17 differentiation during EAE development, suggesting a promising therapeutic application for disease treatment., (Copyright © 2020 Angelou, Wells, Vijayaraghavan, Dougan, Lawlor, Iverson, Lazarevic, Kimura, Peyton, Minter, Osborne, Pobezinskaya and Pobezinsky.)
- Published
- 2020
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17. Ezh2 controls development of natural killer T cells, which cause spontaneous asthma-like pathology.
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Tumes D, Hirahara K, Papadopoulos M, Shinoda K, Onodera A, Kumagai J, Yip KH, Pant H, Kokubo K, Kiuchi M, Aoki A, Obata-Ninomiya K, Tokoyoda K, Endo Y, Kimura MY, and Nakayama T
- Subjects
- Animals, Asthma genetics, Asthma pathology, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors immunology, Enhancer of Zeste Homolog 2 Protein genetics, Immunoglobulin E genetics, Immunoglobulin E immunology, Inflammation genetics, Inflammation immunology, Inflammation pathology, Interleukin-13 genetics, Interleukin-13 immunology, Interleukin-4 genetics, Interleukin-4 immunology, Lung pathology, Mice, Mice, Knockout, Natural Killer T-Cells pathology, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon immunology, Asthma immunology, Enhancer of Zeste Homolog 2 Protein immunology, Lung immunology, Natural Killer T-Cells immunology
- Abstract
Background: Natural killer T (NKT) cells express a T-cell receptor that recognizes endogenous and environmental glycolipid antigens. Several subsets of NKT cells have been identified, including IFN-γ-producing NKT1 cells, IL-4-producing NKT2 cells, and IL-17-producing NKT17 cells. However, little is known about the factors that regulate their differentiation and respective functions within the immune system., Objective: We sought to determine whether the polycomb repressive complex 2 protein enhancer of zeste homolog 2 (Ezh2) restrains pathogenicity of NKT cells in the context of asthma-like lung disease., Methods: Numbers of invariant natural killer T (iNKT) 1, iNKT2, and iNKT17 cells and tissue distribution, cytokine production, lymphoid tissue localization, and transcriptional profiles of iNKT cells from wild-type and Ezh2 knockout (KO) iNKT mice were determined. The contribution of NKT cells to development of spontaneous and house dust mite-induced airways pathology, including airways hyperreactivity (AHR) to methacholine, was also assessed in wild-type, Ezh2 KO, and Ezh2 KO mice lacking NKT cells., Results: Ezh2 restrains development of pathogenic NKT cells, which induce spontaneous asthma-like disease in mice. Deletion of Ezh2 increased production of IL-4 and IL-13 and induced spontaneous AHR, lung inflammation, mucus production, and IgE. Increased IL-4 and IL-13 levels, AHR, lung inflammation, and IgE levels were all dependent on iNKT cells. In house dust mite-exposed animals Ezh2 KO resulted in enhanced AHR that was also dependent on iNKT cells., Conclusion: Ezh2 is a central regulator of iNKT pathogenicity and suppresses the ability of iNKT cells to induce asthma-like pathology., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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18. Survival of Naïve T Cells Requires the Expression of Let-7 miRNAs.
- Author
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Pobezinskaya EL, Wells AC, Angelou CC, Fagerberg E, Aral E, Iverson E, Kimura MY, and Pobezinsky LA
- Subjects
- Animals, DEAD-box RNA Helicases genetics, Lymph Nodes cytology, Mice, Knockout, MicroRNAs genetics, Ribonuclease III genetics, MicroRNAs immunology, T-Lymphocytes immunology
- Abstract
Maintaining the diversity and constant numbers of naïve T cells throughout the organism's lifetime is necessary for efficient immune responses. Naïve T cell homeostasis, which consists of prolonged survival, occasional proliferation and enforcement of quiescence, is tightly regulated by multiple signaling pathways which are in turn controlled by various transcription factors. However, full understanding of the molecular mechanisms underlying the maintenance of the peripheral T cell pool has not been achieved. In the present study, we demonstrate that T cell-specific deficiency in let-7 miRNAs results in peripheral T cell lymphopenia resembling that of Dicer1 knockout mice. Deletion of let-7 leads to profound T cell apoptosis while overexpression prevents it. We further show that in the absence of let-7, T cells cannot sustain optimal levels of the pro-survival factor Bcl2 in spite of the intact IL-7 signaling, and re-expression of Bcl2 in let-7 deficient T cells completely rescues the survival defect. Thus, we have uncovered a novel let-7-dependent mechanism of post-transcriptional regulation of naïve T cell survival in vivo .
- Published
- 2019
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19. A new therapeutic target: the CD69-Myl9 system in immune responses.
- Author
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Kimura MY, Koyama-Nasu R, Yagi R, and Nakayama T
- Subjects
- Animals, Antigens, CD chemistry, Antigens, CD genetics, Antigens, CD immunology, Antigens, Differentiation, T-Lymphocyte chemistry, Antigens, Differentiation, T-Lymphocyte genetics, Antigens, Differentiation, T-Lymphocyte immunology, Cell Transformation, Neoplastic, Disease Susceptibility, Gene Expression, Humans, Inflammation etiology, Inflammation metabolism, Inflammation pathology, Lectins, C-Type chemistry, Lectins, C-Type genetics, Lectins, C-Type immunology, Ligands, Molecular Targeted Therapy, Myosin Light Chains chemistry, Myosin Light Chains genetics, Myosin Light Chains immunology, Neoplasms etiology, Neoplasms metabolism, Neoplasms pathology, Protein Binding, Respiratory Hypersensitivity etiology, Respiratory Hypersensitivity metabolism, Respiratory Hypersensitivity pathology, Structure-Activity Relationship, Antigens, CD metabolism, Antigens, Differentiation, T-Lymphocyte metabolism, Biomarkers, Immunity, Lectins, C-Type metabolism, Myosin Light Chains metabolism
- Abstract
CD69 is an activation marker on leukocytes. Early studies showed that the CD69
+ cells were detected in the lung of patients with asthmatic and eosinophilic pneumonia, suggesting that CD69 might play crucial roles in the pathogenesis of such inflammatory diseases, rather than simply being an activation marker. Intensive studies using mouse models have since clarified that CD69 is a functional molecule regulating the immune responses. We discovered that Myosin light chain 9, 12a, 12b (Myl9/12) are ligands for CD69 and that platelet-derived Myl9 forms a net-like structure (Myl9 nets) that is strongly detected inside blood vessels in inflamed lung. CD69-expressing activated T cells attached to the Myl9 nets can thereby migrate into the inflamed tissues through a system known as the CD69-Myl9 system. In this review, we summarize the discovery of the CD69-Myl9 system and discuss how this system is important in inflammatory immune responses. In addition, we discuss our recent finding that CD69 controls the exhaustion status of tumor-infiltrating T cells and that the blockade of the CD69 function enhances anti-tumor immunity. Finally, we discuss the possibility of CD69 as a new therapeutic target for patients with intractable inflammatory disorders and tumors.- Published
- 2019
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20. Crucial role of CD69 in anti-tumor immunity through regulating the exhaustion of tumor-infiltrating T cells.
- Author
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Mita Y, Kimura MY, Hayashizaki K, Koyama-Nasu R, Ito T, Motohashi S, Okamoto Y, and Nakayama T
- Subjects
- Animals, Breast Neoplasms pathology, Cells, Cultured, Female, Lectins, C-Type deficiency, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Antigens, CD immunology, Antigens, Differentiation, T-Lymphocyte immunology, Breast Neoplasms immunology, Lectins, C-Type immunology, Lymphocytes, Tumor-Infiltrating immunology
- Abstract
The introduction of immune checkpoint inhibitors in cancer treatment highlights the negative regulation of anti-tumor immunity, such as effector T-cell exhaustion in the tumor microenvironment. However, the mechanisms underlying the induction and prevention of T-cell exhaustion remain largely unknown. We found that CD69, a type II glycoprotein known to regulate inflammation through T-cell migration and retention in tissues, plays an important role in inducing the exhaustion of tumor-infiltrating T cells. Cd69-/- mice showed reduced tumor growth and metastasis in a 4T1-luc2 murine breast cancer model, in which increased numbers of tumor-infiltrating lymphocytes, relatively little T-cell exhaustion, and enhanced IFNγ production were observed. Anti-CD69 monoclonal antibody treatment attenuated the T-cell exhaustion and tumor progression in tumor-bearing mice. These findings highlight a novel role of CD69 in controlling the tumor immune escape mediated by T-cell exhaustion and indicate that CD69 is a novel target for cancer immunotherapy.
- Published
- 2018
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21. CD69 prevents PLZF hi innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation.
- Author
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Kimura MY, Igi A, Hayashizaki K, Mita Y, Shinzawa M, Kadakia T, Endo Y, Ogawa S, Yagi R, Motohashi S, Singer A, and Nakayama T
- Subjects
- Animals, CD24 Antigen metabolism, Cell Differentiation, Gene Expression Regulation, Mice, Mice, Knockout, Natural Killer T-Cells metabolism, Promyelocytic Leukemia Zinc Finger Protein metabolism, Sphingosine-1-Phosphate Receptors, T-Lymphocyte Subsets metabolism, Thymocytes metabolism, Antigens, CD genetics, Antigens, Differentiation, T-Lymphocyte genetics, Lectins, C-Type genetics, Lymphopoiesis genetics, Natural Killer T-Cells cytology, Receptors, Lysosphingolipid genetics, T-Lymphocyte Subsets cytology, Thymocytes cytology
- Abstract
While CD69 may regulate thymocyte egress by inhibiting S1P
1 expression, CD69 expression is not thought to be required for normal thymocyte development. Here we show that CD69 is in fact specifically required for the differentiation of mature NKT2 cells, which do not themselves express CD69. Mechanistically, CD69 expression is required on CD24+ PLZFhi innate precursors for their retention in the thymus and completion of their differentiation into mature NKT2 cells. By contrast, CD69-deficient CD24+ PLZFhi innate precursors express S1P1 and prematurely exit the thymus, while S1P1 inhibitor treatment of CD69-deficient mice retains CD24+ PLZFhi innate precursors in the thymus and restores NKT2 cell differentiation. Thus, CD69 prevents S1P1 expression on CD24+ PLZFhi innate precursor cells from aborting NKT2 differentiation in the thymus. This study reveals the importance of CD69 to prolong the thymic residency time of developing immature precursors for proper differentiation of a T cell subset.- Published
- 2018
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22. Crucial role for CD69 in allergic inflammatory responses: CD69-Myl9 system in the pathogenesis of airway inflammation.
- Author
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Kimura MY, Hayashizaki K, Tokoyoda K, Takamura S, Motohashi S, and Nakayama T
- Subjects
- Animals, Antigens, CD chemistry, Antigens, CD genetics, Antigens, Differentiation, T-Lymphocyte chemistry, Antigens, Differentiation, T-Lymphocyte genetics, Disease Models, Animal, Disease Susceptibility, Gene Expression Regulation, Humans, Hypersensitivity drug therapy, Inflammation etiology, Inflammation metabolism, Lectins, C-Type chemistry, Lectins, C-Type genetics, Protein Binding, Protein Interaction Domains and Motifs, Respiratory Hypersensitivity drug therapy, Respiratory Hypersensitivity etiology, Respiratory Hypersensitivity metabolism, Signal Transduction, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Antigens, CD metabolism, Antigens, Differentiation, T-Lymphocyte metabolism, Hypersensitivity etiology, Hypersensitivity metabolism, Lectins, C-Type metabolism, Myosin Light Chains metabolism
- Abstract
CD69 has been known as an early activation marker of lymphocytes; whereas, recent studies demonstrate that CD69 also has critical functions in immune responses. Early studies using human samples revealed the involvement of CD69 in various inflammatory diseases including asthma. Moreover, murine disease models using Cd69
-/- mice and/or anti-CD69 antibody (Ab) treatment have revealed crucial roles for CD69 in inflammatory responses. However, it had not been clear how the CD69 molecule contributes to the pathogenesis of inflammatory diseases. We recently elucidated a novel mechanism, in which the interaction between CD69 and its ligands, myosin light chain 9, 12a and 12b (Myl9/12) play a critical role in the recruitment of activated T cells into the inflammatory lung. In this review, we first summarize CD69 function based on its structure and then introduce the evidence for the involvement of CD69 in human diseases and murine disease models. Then, we will describe how we discovered CD69 ligands, Myl9 and Myl12, and how the CD69-Myl9 system regulates airway inflammation. Finally, we will discuss possible therapeutic usages of the blocking Ab to the CD69-Myl9 system., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)- Published
- 2017
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23. Timing and duration of MHC I positive selection signals are adjusted in the thymus to prevent lineage errors.
- Author
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Kimura MY, Thomas J, Tai X, Guinter TI, Shinzawa M, Etzensperger R, Li Z, Love P, Nakayama T, and Singer A
- Subjects
- Animals, Cell Differentiation, Cell Lineage, Cells, Cultured, Core Binding Factor Alpha 3 Subunit genetics, Cytokines metabolism, Histocompatibility Antigens Class I genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Receptors, Antigen, T-Cell metabolism, Signal Transduction, Transcription Factors, CD8-Positive T-Lymphocytes physiology, Clonal Selection, Antigen-Mediated, Core Binding Factor Alpha 3 Subunit metabolism, Histocompatibility Antigens Class I metabolism, Thymus Gland immunology
- Abstract
Major histocompatibility complex class I (MHC I) positive selection of CD8
+ T cells in the thymus requires that T cell antigen receptor (TCR) signaling end in time for cytokines to induce Runx3d, the CD8-lineage transcription factor. We examined the time required for these events and found that the overall duration of positive selection was similar for all CD8+ thymocytes in mice, despite markedly different TCR signaling times. Notably, prolonged TCR signaling times were counter-balanced by accelerated Runx3d induction by cytokines and accelerated differentiation into CD8+ T cells. Consequently, lineage errors did not occur except when MHC I-TCR signaling was so prolonged that the CD4-lineage-specifying transcription factor ThPOK was expressed, preventing Runx3d induction. Thus, our results identify a compensatory signaling mechanism that prevents lineage-fate errors by dynamically modulating Runx3d induction rates during MHC I positive selection.- Published
- 2016
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24. Myosin light chains 9 and 12 are functional ligands for CD69 that regulate airway inflammation.
- Author
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Hayashizaki K, Kimura MY, Tokoyoda K, Hosokawa H, Shinoda K, Hirahara K, Ichikawa T, Onodera A, Hanazawa A, Iwamura C, Kakuta J, Muramoto K, Motohashi S, Tumes DJ, Iinuma T, Yamamoto H, Ikehara Y, Okamoto Y, and Nakayama T
- Abstract
Recent decades have witnessed a rapid worldwide increase in chronic inflammatory disorders such as asthma. CD4
+ T helper 2 cells play critical roles in the pathogenesis of allergic airway inflammation, and CD69 expression on activated CD4 T cells is required to induce allergic inflammation in tissues. However, how CD69 mechanistically controls allergic inflammation remains poorly defined. In lymphoid tissues, CD69 regulates cellular retention through inhibition of S1P1 expression and requires no specific ligands to function. In contrast, we show herein that myosin light chain (Myl) 9 and Myl12 are new functional ligands for CD69. Blockade of CD69-Myl9/12 interaction ameliorates allergic airway inflammation in ovalbumin-induced and house dust mite-induced mouse models of asthma. Within the inflamed mouse airways, we found that the expression of Myl9/12 was increased and that platelet-derived Myl9/12 localized to the luminal surface of blood vessels and formed intravascular net-like structures. Analysis of nasal polyps of eosinophilic chronic rhinosinusitis patients revealed that Myl9/12 expression was increased in inflammatory lesions and was distributed within net-like structures in the intravascular space. In addition, we detected Myl9/12 in perivascular spaces where many CD69+ cells were positioned within Myl9/12 structures. Thus, CD69-Myl9/12 interaction is a key event in the recruitment of activated CD69+ T cells to inflamed tissues and could be a therapeutic target for intractable airway inflammatory diseases., (Copyright © 2016, American Association for the Advancement of Science.)- Published
- 2016
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25. Methylation of Gata3 protein at Arg-261 regulates transactivation of the Il5 gene in T helper 2 cells.
- Author
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Hosokawa H, Kato M, Tohyama H, Tamaki Y, Endo Y, Kimura MY, Tumes DJ, Motohashi S, Matsumoto M, Nakayama KI, Tanaka T, and Nakayama T
- Subjects
- Amino Acid Sequence, Animals, Arginine metabolism, Blotting, Western, Cell Differentiation, Cell Proliferation, Cells, Cultured, Chaperonin 60 antagonists & inhibitors, Chaperonin 60 genetics, Chaperonin 60 metabolism, Chromatin Assembly and Disassembly, Chromatin Immunoprecipitation, Cytokines genetics, Cytokines metabolism, Flow Cytometry, Fluorescent Antibody Technique, GATA3 Transcription Factor metabolism, Immunoprecipitation, Interleukin-5 metabolism, Mice, Mice, Inbred C57BL, Mitochondrial Proteins antagonists & inhibitors, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Molecular Sequence Data, Promoter Regions, Genetic genetics, RNA, Messenger genetics, RNA, Small Interfering genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid, Th1 Cells immunology, Th1 Cells metabolism, Th2 Cells immunology, Arginine genetics, DNA Methylation, GATA3 Transcription Factor genetics, Interleukin-5 genetics, Th2 Cells metabolism, Transcriptional Activation
- Abstract
Gata3 acts as a master regulator for T helper 2 (Th2) cell differentiation by inducing chromatin remodeling of the Th2 cytokine loci, accelerating Th2 cell proliferation, and repressing Th1 cell differentiation. Gata3 also directly transactivates the interleukin-5 (Il5) gene via additional mechanisms that have not been fully elucidated. We herein identified a mechanism whereby the methylation of Gata3 at Arg-261 regulates the transcriptional activation of the Il5 gene in Th2 cells. Although the methylation-mimicking Gata3 mutant retained the ability to induce IL-4 and repress IFNγ production, the IL-5 production was selectively impaired. We also demonstrated that heat shock protein (Hsp) 60 strongly associates with the methylation-mimicking Gata3 mutant and negatively regulates elongation of the Il5 transcript by RNA polymerase II. Thus, arginine methylation appears to play a pivotal role in the organization of Gata3 complexes and the target gene specificity of Gata3., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2015
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26. Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function.
- Author
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Pobezinsky LA, Etzensperger R, Jeurling S, Alag A, Kadakia T, McCaughtry TM, Kimura MY, Sharrow SO, Guinter TI, Feigenbaum L, and Singer A
- Subjects
- Animals, Cell Differentiation genetics, Cell Lineage genetics, Cytotoxicity, Immunologic genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, MicroRNAs genetics, Promyelocytic Leukemia Zinc Finger Protein, Protein Binding, RNA Processing, Post-Transcriptional, Tretinoin metabolism, Up-Regulation, Vitamin D metabolism, Cytokines metabolism, Kruppel-Like Transcription Factors metabolism, MicroRNAs metabolism, Natural Killer T-Cells physiology, Thymocytes physiology
- Abstract
Lethal-7 (let-7) microRNAs (miRNAs) are the most abundant miRNAs in the genome, but their role in developing thymocytes is unclear. We found that let-7 miRNAs targeted Zbtb16 mRNA, which encodes the lineage-specific transcription factor PLZF, to post-transcriptionally regulate PLZF expression and thereby the effector functions of natural killer T cells (NKT cells). Dynamic upregulation of let-7 miRNAs during the development of NKT thymocytes downregulated PLZF expression and directed their terminal differentiation into interferon-γ (IFN-γ)-producing NKT1 cells. Without upregulation of let-7 miRNAs, NKT thymocytes maintained high PLZF expression and terminally differentiated into interleukin 4 (IL-4)-producing NKT2 cells or IL-17-producing NKT17 cells. Upregulation of let-7 miRNAs in developing NKT thymocytes was signaled by IL-15, vitamin D and retinoic acid. Such targeting of a lineage-specific transcription factor by miRNA represents a previously unknown level of developmental regulation in the thymus.
- Published
- 2015
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27. The transcription factor ThPOK suppresses Runx3 and imposes CD4(+) lineage fate by inducing the SOCS suppressors of cytokine signaling.
- Author
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Luckey MA, Kimura MY, Waickman AT, Feigenbaum L, Singer A, and Park JH
- Subjects
- Animals, CD8-Positive T-Lymphocytes physiology, Mice, Mice, Inbred C57BL, CD4-Positive T-Lymphocytes physiology, Cell Lineage, Core Binding Factor Alpha 3 Subunit physiology, Suppressor of Cytokine Signaling Proteins genetics, Transcription Factors physiology
- Abstract
Lineage fate in the thymus is determined by mutually exclusive expression of the transcription factors ThPOK and Runx3, with ThPOK imposing the CD4(+) lineage fate and Runx3 promoting the CD8(+) lineage fate. While it is known that cytokine signals induce thymocytes to express Runx3, it is not known how ThPOK prevents thymocytes from expressing Runx3 and adopting the CD8(+) lineage fate, nor is it understood why ThPOK itself imposes the CD4(+) lineage fate on thymocytes. We now report that genes encoding members of the SOCS (suppressor of cytokine signaling) family are critical targets of ThPOK and that their induction by ThPOK represses Runx3 expression and promotes the CD4(+) lineage fate. Thus, induction of SOCS-encoding genes is the main mechanism by which ThPOK imposes the CD4(+) lineage fate in the thymus.
- Published
- 2014
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28. Lck availability during thymic selection determines the recognition specificity of the T cell repertoire.
- Author
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Van Laethem F, Tikhonova AN, Pobezinsky LA, Tai X, Kimura MY, Le Saout C, Guinter TI, Adams A, Sharrow SO, Bernhardt G, Feigenbaum L, and Singer A
- Subjects
- Animals, Major Histocompatibility Complex, Mice, Receptors, Antigen, T-Cell, alpha-beta, Receptors, Virus, Signal Transduction, T-Lymphocytes metabolism, Thymus Gland immunology, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) metabolism, T-Lymphocytes cytology, Thymocytes metabolism, Thymus Gland metabolism
- Abstract
Thymic selection requires signaling by the protein tyrosine kinase Lck to generate T cells expressing αβ T cell antigen receptors (TCR). For reasons not understood, the thymus selects only αβTCR that are restricted by major histocompatibility complex (MHC)-encoded determinants. Here, we report that Lck proteins that were coreceptor associated promoted thymic selection of conventionally MHC-restricted TCR, but Lck proteins that were coreceptor free promoted thymic selection of MHC-independent TCR. Transgenic TCR with MHC-independent specificity for CD155 utilized coreceptor-free Lck to signal thymic selection in the absence of MHC, unlike any transgenic TCR previously described. Thus, the thymus can select either MHC-restricted or MHC-independent αβTCR depending on whether Lck is coreceptor associated or coreceptor free. We conclude that the intracellular state of Lck determines the specificity of thymic selection and that Lck association with coreceptor proteins during thymic selection is the mechanism by which MHC restriction is imposed on a randomly generated αβTCR repertoire., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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29. IL-7 signaling must be intermittent, not continuous, during CD8⁺ T cell homeostasis to promote cell survival instead of cell death.
- Author
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Kimura MY, Pobezinsky LA, Guinter TI, Thomas J, Adams A, Park JH, Tai X, and Singer A
- Subjects
- Animals, CD8-Positive T-Lymphocytes cytology, Cell Death immunology, Cell Proliferation, Cell Survival immunology, Gene Expression Regulation, Interferon-gamma biosynthesis, Interferon-gamma immunology, Interleukin-7 immunology, Lymphocyte Activation, Mice, Mice, Transgenic, Receptors, Antigen, T-Cell immunology, Time Factors, CD8-Positive T-Lymphocytes immunology, Homeostasis immunology, Interleukin-7 genetics, Receptors, Antigen, T-Cell genetics, Signal Transduction immunology
- Abstract
The maintenance of naive CD8(+) T cells is necessary for lifelong immunocompetence but for unknown reasons requires signaling via both interleukin 7 (IL-7) and the T cell antigen receptor (TCR). We now report that naive CD8(+) T cells required IL-7 signaling to be intermittent, not continuous, because prolonged IL-7 signaling induced naive CD8(+) T cells to proliferate, produce interferon-γ (IFN-γ) and undergo IFN-γ-triggered cell death. Homeostatic engagement of the TCR interrupted IL-7 signaling and thereby supported the survival and quiescence of CD8(+) T cells. However, CD8(+) T cells with insufficient TCR affinity for self ligands received prolonged IL-7 signaling and died during homeostasis. In this study we identified regulation of the duration of IL-7 signaling by homeostatic engagement of the TCR as the basis for in vivo CD8(+) T cell homeostasis.
- Published
- 2013
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30. Polycomb group gene product Ring1B regulates Th2-driven airway inflammation through the inhibition of Bim-mediated apoptosis of effector Th2 cells in the lung.
- Author
-
Suzuki A, Iwamura C, Shinoda K, Tumes DJ, Kimura MY, Hosokawa H, Endo Y, Horiuchi S, Tokoyoda K, Koseki H, Yamashita M, and Nakayama T
- Subjects
- Animals, Apoptosis genetics, Apoptosis Regulatory Proteins deficiency, Apoptosis Regulatory Proteins physiology, Bcl-2-Like Protein 11, Cells, Cultured, Down-Regulation genetics, Down-Regulation immunology, Immunophenotyping, Lung metabolism, Membrane Proteins deficiency, Membrane Proteins physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Polycomb Repressive Complex 1, Polycomb-Group Proteins, Proto-Oncogene Proteins deficiency, Proto-Oncogene Proteins physiology, Th2 Cells metabolism, Th2 Cells pathology, Apoptosis immunology, Apoptosis Regulatory Proteins antagonists & inhibitors, Inflammation Mediators physiology, Lung immunology, Lung pathology, Membrane Proteins antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors, Repressor Proteins physiology, Th2 Cells immunology
- Abstract
Polycomb group (PcG) gene products regulate the maintenance of homeobox gene expression in Drosophila and vertebrates. In the immune system, PcG molecules control cell cycle progression of thymocytes, Th2 cell differentiation, and the generation of memory CD4 T cells. In this paper, we extended the study of PcG molecules to the regulation of in vivo Th2 responses, especially allergic airway inflammation, by using conditional Ring1B-deficient mice with a CD4 T cell-specific deletion of the Ring1B gene (Ring1B(-/-) mice). In Ring1B(-/-) mice, CD4 T cell development appeared to be normal, whereas the differentiation of Th2 cells but not Th1 cells was moderately impaired. In an Ag-induced Th2-driven allergic airway inflammation model, eosinophilic inflammation was attenuated in Ring1B(-/-) mice. Interestingly, Ring1B(-/-) effector Th2 cells were highly susceptible to apoptosis in comparison with wild-type effector Th2 cells in vivo and in vitro. The in vitro experiments revealed that the expression of Bim was increased at both the transcriptional and protein levels in Ring1B(-/-) effector Th2 cells, and the enhanced apoptosis in Ring1B(-/-) Th2 cells was rescued by the knockdown of Bim but not the other proapoptotic genes, such as Perp, Noxa, or Bax. The enhanced apoptosis detected in the transferred Ring1B(-/-) Th2 cells in the lung of the recipient mice was also rescued by knockdown of Bim. Therefore, these results indicate that Ring1B plays an important role in Th2-driven allergic airway inflammation through the control of Bim-dependent apoptosis of effector Th2 cells in vivo.
- Published
- 2010
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31. Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells.
- Author
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Park JH, Adoro S, Guinter T, Erman B, Alag AS, Catalfamo M, Kimura MY, Cui Y, Lucas PJ, Gress RE, Kubo M, Hennighausen L, Feigenbaum L, and Singer A
- Subjects
- Animals, Cell Count, Cell Differentiation immunology, Cell Lineage, Core Binding Factor Alpha 3 Subunit immunology, Flow Cytometry, Interleukin-7 immunology, Mice, Mice, Knockout, Mice, Transgenic, STAT5 Transcription Factor immunology, Signal Transduction, Cytokines immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Immature CD4(+)CD8(+) (double-positive (DP)) thymocytes are signaled via T cell antigen receptors (TCRs) to undergo positive selection and become responsive to intrathymic cytokines such as interleukin 7 (IL-7). We report here that cytokine signaling is required for positively selected thymocytes to express the transcription factor Runx3, specify CD8 lineage choice and differentiate into cytotoxic-lineage T cells. In DP thymocytes genetically engineered to be cytokine responsive, IL-7 signaling induced TCR-unsignaled DP thymocytes to express Runx3 and to differentiate into mature CD8(+) T cells, completely circumventing positive selection. We conclude that TCR-mediated positive selection converts DP cells into cytokine-responsive thymocytes, but it is subsequent signaling by intrathymic cytokines that specifies CD8 lineage choice and promotes differentiation into cytotoxic-lineage T cells.
- Published
- 2010
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32. Memory Th1/Th2 cell generation controlled by Schnurri-2.
- Author
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Nakayama T and Kimura MY
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, Cell Transplantation, DNA-Binding Proteins genetics, Mice, Multigene Family, NF-kappa B immunology, DNA-Binding Proteins physiology, Immunologic Memory immunology, Th1 Cells immunology, Th2 Cells immunology
- Abstract
Schnurri (Shn) is a large zinc-finger containingprotein, which plays a critical role in cell growth, signal transduction and lymphocyte development. There are three orthologues (Shn-1, Shn-2 and Shn-3) in vertebrates. In Shn-2-deficient mice, the activation of NF-kappaB in CD4 T cells is upregulated and their ability to differentiate into Th2 cells is enhanced in part through the increased expression of GATA3. Shn-2 is found to compete with p50 NF-kappaB for binding to a consensus NF-kappaB motif and inhibit the NF-kappaB-driven promoter activity. In addition, Th2-driven allergic airway inflammation was enhanced in Shn-2-deficient mice. Therefore, Shn-2 appears to negatively control the differentiation of Th2 cells and Th2 responses through the repression of NF-kappaB function. Memory Th1/Th2 cells are not properly generated from Shn-2-deficient effector Th1/Th2 cells. The expression levels of CD69 and the number ofapoptotic cells are selectively increased in Shn-2-deficient Thl/Th2 cells when they are transferred into syngeneic host animals, in which memoryh Th1/Th2 cells are generated within a month. In addition, an increased susceptibility to apoptotic cell death is also observed in vitro accompanied with the increased expression of FasL, one of the NF-kappaB-dependent genes. Th2 effector cells overexpressing the p65 subunit of NF-kappaB demonstrate a decreased cell survival particularly in the lymph node. These results indicate that Shn-2-mediated repression of NF-kappaB is required for cell survival and the successful generation of memory Th1/Th2 cells. This may point to the possibility that after antigen clearance the recovery of the quiescent state in effector Th cells is required for the generation of memory Th cells. A repressor molecule Shn-2 plays an important role in this process.
- Published
- 2010
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33. Schnurri-2 regulates Th2-dependent airway inflammation and airway hyperresponsiveness.
- Author
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Iwamura C, Kimura MY, Shinoda K, Endo Y, Hasegawa A, Yamashita M, and Nakayama T
- Subjects
- Adoptive Transfer, Animals, Asthma immunology, Asthma pathology, Asthma physiopathology, Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid cytology, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes pathology, Cell Count, Chemokine CCL17, Chemokine CCL22, Chemokines, CC genetics, Chemokines, CC metabolism, DNA-Binding Proteins physiology, Eosinophils metabolism, Eosinophils pathology, Flow Cytometry, Gene Expression, Interleukin-13 metabolism, Interleukin-5 metabolism, Lung metabolism, Lung pathology, Lung physiopathology, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Ovalbumin immunology, Pneumonia pathology, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta immunology, Respiratory Hypersensitivity pathology, Respiratory Hypersensitivity physiopathology, Th2 Cells transplantation, Vaccination, DNA-Binding Proteins genetics, Pneumonia immunology, Respiratory Hypersensitivity immunology, Th2 Cells immunology
- Abstract
Schnurri (Shn)-2 is a large zinc finger-containing protein, which plays a critical role in cell growth, signal transduction and lymphocyte development. In Shn-2-deficient (Shn-2(-/-)) CD4 T cells, the activation of nuclear factor-kappaB is up-regulated and their ability to differentiate into Th2 is enhanced. Here, we extend our investigation and demonstrate that Shn-2 regulates Th2 responses in vivo using an ovalbumin-induced allergic asthma model. Eosinophilic inflammation, mucus hyperproduction and airway hyperresponsiveness (AHR) were all enhanced in Shn-2(-/-) mice. Moreover, eosinophilic infiltration and AHR were enhanced in mice given a transfer of Shn-2(-/-) effector Th2. Shn-2 in Th2 is thus considered to play an important role as a negative regulator in allergic airway inflammation.
- Published
- 2007
- Full Text
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34. Schnurri-2 controls memory Th1 and Th2 cell numbers in vivo.
- Author
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Kimura MY, Iwamura C, Suzuki A, Miki T, Hasegawa A, Sugaya K, Yamashita M, Ishii S, and Nakayama T
- Subjects
- Adoptive Transfer, Animals, Antigens, CD biosynthesis, Antigens, Differentiation, T-Lymphocyte biosynthesis, Apoptosis, Lectins, C-Type, Lymphocyte Count, Mice, Mice, Inbred BALB C, Transcription Factor RelA physiology, fas Receptor biosynthesis, DNA-Binding Proteins physiology, Immunologic Memory, Th1 Cells physiology, Th2 Cells physiology
- Abstract
Schnurri-2 (Shn-2) is a large zinc-finger containing protein, and it plays a critical role in cell growth, signal transduction and lymphocyte development. In Shn-2-deficient CD4 T cells, the activation of NF-kappaB was up-regulated and their ability to differentiate into Th2 cells was enhanced. We herein demonstrate that Th1 and Th2 memory cells are not properly generated from Shn-2-deficient effector Th1/Th2 cells. Even a week after the transfer of effector Th1/Th2 cells into syngeneic mice, a dramatic decrease in the number of Shn-2-deficient donor T cells was detected particularly in the lymphoid organs. The transferred Shn-2-deficient Th1/Th2 cells express higher levels of the activation marker CD69. No significant defect in the BrdU incorporation in the Shn-2-deficient transferred CD4 T cells was observed. The numbers of apoptotic cells were selectively higher in Shn-2-deficient donor Th1/Th2 cell population. Moreover, Shn-2-deficient effector Th1 and Th2 cells showed an increased susceptibility to cell death in in vitro cultures with increased expression of FasL. Transfer of Th2 effector cells over-expressing the p65 subunit of NF-kappaB resulted in a decreased number of p65-expressing cells in the lymphoid organs. As expected, T cell-dependent Ab responses after in vivo immunization of Shn-2-deficient mice were significantly reduced. Thus, Shn-2 appears to control the generation of memory Th1/Th2 cells through a change in their susceptibility to cell death.
- Published
- 2007
- Full Text
- View/download PDF
35. Chromatin remodeling at the Th2 cytokine gene loci in human type 2 helper T cells.
- Author
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Kaneko T, Hosokawa H, Yamashita M, Wang CR, Hasegawa A, Kimura MY, Kitajiama M, Kimura F, Miyazaki M, and Nakayama T
- Subjects
- Acetylation, Histones metabolism, Humans, Interleukin-5 genetics, Lysine metabolism, Methylation, RNA, Messenger genetics, RNA, Messenger metabolism, Th1 Cells metabolism, Transcription Factors genetics, Transcription Factors metabolism, Chromatin Assembly and Disassembly genetics, Cytokines genetics, Th2 Cells metabolism
- Abstract
The differentiation of mouse naïve CD4 T cells into type 2 helper (Th2) cells is accompanied by chromatin remodeling at the nucleosomes associated with the IL-4, IL-13 and IL-5 genes. However, little is known about how chromatin remodeling of these Th2 cytokine gene loci occurs in human Th2 cells. We herein established an in vitro culture system in which both Th1 and Th2 cells are efficiently differentiated from human peripheral blood naïve CD4 T cells. This system allowed us to investigate the chromatin status at the Th2 cytokine gene loci and the IFNgamma locus in human Th2 and Th1 cells, respectively. In typical individuals, the chromatin remodeling indicated by the induction of hyper-acetylation of histone H3 lysine 9 and hyper-methylation of histone H3 lysine 4 was induced at the whole Th2 cytokine gene loci in developing Th2 cells. We more precisely assessed the methylation status of histone H3 lysine 4 at the Th2 cytokine gene loci (IL-5 exon 3, IL-5 promoter, IL-5/RAD50 intergenic region, RAD50 promoter, CGRE, CNS1, IL-13 promoter, IL-4 promoter, and VA enhancer regions) and the IFNgamma locus in developing Th1 and Th2 cells prepared from 20 healthy volunteers. Th2-cell specific chromatin remodeling was induced at most of the Th2 cytokine gene loci. In parallel with the induction of chromatin remodeling, GATA3 mRNA was preferentially expressed in developing Th2 cells, whereas T-bet, HLX and ROG mRNA was selectively expressed in developing Th1 cells.
- Published
- 2007
- Full Text
- View/download PDF
36. Regulation of Th2 cell development by Polycomb group gene bmi-1 through the stabilization of GATA3.
- Author
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Hosokawa H, Kimura MY, Shinnakasu R, Suzuki A, Miki T, Koseki H, van Lohuizen M, Yamashita M, and Nakayama T
- Subjects
- Animals, Cells, Cultured, DNA-Binding Proteins immunology, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, GATA3 Transcription Factor immunology, Immunoblotting, Immunoprecipitation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Nuclear Proteins immunology, Polycomb Repressive Complex 1, Proto-Oncogene Proteins immunology, Repressor Proteins immunology, Reverse Transcriptase Polymerase Chain Reaction, Th1 Cells cytology, Cell Differentiation immunology, DNA-Binding Proteins metabolism, GATA3 Transcription Factor metabolism, Nuclear Proteins metabolism, Proto-Oncogene Proteins metabolism, Repressor Proteins metabolism, Th2 Cells cytology
- Abstract
The Polycomb group (PcG) gene products regulate the maintenance of the homeobox gene expression in Drosophila and vertebrates and also the cell cycle progression in thymocytes and Th2 cell differentiation in mature T cells. We herein studied the role of PcG gene bmi-1 product in Th1/Th2 cell differentiation and found that Bmi-1 facilitates Th2 cell differentiation in a Ring finger-dependent manner. Biochemical studies indicate that Bmi-1 interacts with GATA3 in T cells, which is dependent on the Ring finger of Bmi-1. The overexpression of Bmi-1 resulted in a decreased ubiquitination and an increased protein stability of GATA3. In bmi-1-deficient Th cells, the levels of Th2 cell differentiation decreased as the degradation and ubiquitination on GATA3 increased. Therefore, Bmi-1 plays a crucial role in the control of Th2 cell differentiation in a Ring finger-dependent manner by regulating GATA3 protein stability.
- Published
- 2006
- Full Text
- View/download PDF
37. Hyperresponsive TH2 cells with enhanced nuclear factor-kappa B activation induce atopic dermatitis-like skin lesions in Nishiki-nezumi Cinnamon/Nagoya mice.
- Author
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Tenda Y, Yamashita M, Kimura MY, Hasegawa A, Shimizu C, Kitajima M, Onodera A, Suzuki A, Seki N, and Nakayama T
- Subjects
- Animals, Cell Differentiation immunology, Cytokines biosynthesis, Dermatitis, Atopic metabolism, Lymph Nodes immunology, Lymph Nodes pathology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred Strains, Mites immunology, Species Specificity, Th1 Cells cytology, Th1 Cells immunology, Th1 Cells metabolism, Th1 Cells transplantation, Th2 Cells transplantation, Dermatitis, Atopic immunology, Dermatitis, Atopic pathology, NF-kappa B physiology, Th2 Cells immunology, Th2 Cells metabolism
- Abstract
Background: Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) mice raised in nonair-controlled conventional circumstances spontaneously develop atopic dermatitis-like skin lesions; however, the underlying mechanisms remain unclear., Objective: We wanted to identify the critical intracellular signaling molecules in T cells that induce atopic dermatitis-like skin legions in NC/Nga mice., Methods: We examined the levels of signal transduction and cytokine production in T cells, particularly those in atopic dermatitis-like lesions induced by the topical injection of mite antigens in NC/Nga mice under specific pathogen-free conditions., Results: In NC/Nga mice maintained under specific pathogen-free conditions, the capability of T(H)1/T(H)2 and T cytotoxic 1/T cytotoxic 2 (Tc1/Tc2) cell differentiation increased significantly. T-cell antigen receptor-mediated activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase cascade and nuclear factor-kappaB (NF-kappaB) signaling were enhanced in NC/Nga T cells. The expression of T(H)2 cytokines (IL-4, IL-13, and IL-5) and that of GATA-binding protein 3 (GATA3), avian musculoaponeurotic fibrosarcoma (c-Maf), NF-kappaB, and activator protein 1 (AP1) selectively increased in draining lymph node T cells of NC/Nga mice. Moreover, the cell transfer of inhibitory NF-kappaB mutant-infected T(H)2 cells reduced ear thickness in the mite antigen-induced skin lesion of NC/Nga mice., Conclusion: Hyperresponsive T(H)2 cells with an enhanced activity of NF-kappaB and AP1 play a crucial role in the pathogenesis of atopic dermatitis-like skin lesions in NC/Nga mice., Clinical Implications: These results indicate potential therapeutic usefulness of developing selective inhibitors for NF-kappaB in the treatment of human atopic dermatitis.
- Published
- 2006
- Full Text
- View/download PDF
38. Crucial role of MLL for the maintenance of memory T helper type 2 cell responses.
- Author
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Yamashita M, Hirahara K, Shinnakasu R, Hosokawa H, Norikane S, Kimura MY, Hasegawa A, and Nakayama T
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cytokines biosynthesis, Cytokines immunology, Enzyme-Linked Immunosorbent Assay, GATA3 Transcription Factor genetics, GATA3 Transcription Factor immunology, GATA3 Transcription Factor metabolism, Histones genetics, Hypersensitivity, Immunoblotting, In Situ Hybridization, Lung Diseases immunology, Lung Diseases metabolism, Lung Diseases pathology, Mice, Mice, Transgenic, Myeloid-Lymphoid Leukemia Protein genetics, Myeloid-Lymphoid Leukemia Protein metabolism, RNA, Messenger analysis, Reverse Transcriptase Polymerase Chain Reaction, Th2 Cells metabolism, Immunologic Memory, Inflammation immunology, Myeloid-Lymphoid Leukemia Protein immunology, Th2 Cells immunology
- Abstract
The Mixed-Lineage Leukemia (MLL) gene, a mammalian homolog of the Drosophila trithorax, is implicated in regulating the maintenance of Hox gene expression and hematopoiesis. The physiological functions of MLL in the immune system remain largely unknown. Although MLL(+/-) CD4 T cells differentiate normally into antigen-specific effector Th1/Th2 cells in vitro, the ability of memory Th2 cells to produce Th2 cytokines was selectively reduced. Furthermore, histone modifications at the Th2 cytokine gene loci were not properly maintained in MLL(+/-) memory Th2 cells. The reduced expression of MLL in memory Th2 cells resulted in decreased GATA3 expression accompanied with impaired GATA3 locus histone modifications. The direct association of MLL with the GATA3 locus and the Th2 cytokine gene loci was demonstrated. Memory Th2 cell-dependent allergic airway inflammation was decreased in MLL(+/-) Th2 cell-transferred mice. Thus, a crucial role for MLL in the maintenance of memory Th2 cell function is indicated.
- Published
- 2006
- Full Text
- View/download PDF
39. Impaired GATA3-dependent chromatin remodeling and Th2 cell differentiation leading to attenuated allergic airway inflammation in aging mice.
- Author
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Hasegawa A, Miki T, Hosokawa H, Hossain MB, Shimizu C, Hashimoto K, Kimura MY, Yamashita M, and Nakayama T
- Subjects
- Animals, Antibodies immunology, Antibody Formation, Cells, Cultured, Cytokines biosynthesis, Cytokines genetics, Eosinophils drug effects, Inflammation chemically induced, Inflammation immunology, Inflammation pathology, Lung Diseases chemically induced, Mice, Ovalbumin pharmacology, Phenotype, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, Respiratory Hypersensitivity pathology, Spleen metabolism, Th1 Cells cytology, Th2 Cells cytology, Aging immunology, Cell Differentiation, Chromatin Assembly and Disassembly, GATA3 Transcription Factor metabolism, Lung Diseases metabolism, Respiratory Hypersensitivity immunology, Th2 Cells immunology
- Abstract
Age-related changes in lymphocytes are most prominent in the T cell compartment. There have been substantial numbers of reports on T cell function in aged mice and humans, such as on the production of Th1 and Th2 cytokines, but the results show considerable variation and contradictions. In the present study, we used 8- to 12-mo-old aging mice and a well-established in vitro Th1/Th2 cell differentiation culture system to identify molecular defects in Th1/Th2 cell differentiation that can be detected in the relatively early stages of aging. The capability to differentiate into Th2 cells is reduced in aging mouse CD4(+) T cells. Decreased activation of the ERK MAPK cascade upon TCR stimulation, but normal intracellular-free calcium ion concentration mobilization and normal IL-4-induced STAT6 activation were observed in aging mouse CD4(+) T cells. In addition, reduced expression of GATA3 was detected in developing Th2 cells. Chromatin remodeling of the Th2 cytokine gene locus was found to be impaired. Th2-dependent allergic airway inflammation was milder in aging mice compared with in young adult mice. These results suggest that the levels of Th2 cell differentiation and resulting Th2-dependent immune responses, including allergic airway inflammation, decline during aging through defects in the activation of the ERK MAPK cascade, expression of GATA3 protein and GATA3-dependent chromatin remodeling of the Th2 cytokine gene locus. In the present study, we provide the first evidence indicating that a chromatin-remodeling event in T cells is impaired by aging.
- Published
- 2006
- Full Text
- View/download PDF
40. Regulation of T helper type 2 cell differentiation by murine Schnurri-2.
- Author
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Kimura MY, Hosokawa H, Yamashita M, Hasegawa A, Iwamura C, Watarai H, Taniguchi M, Takagi T, Ishii S, and Nakayama T
- Subjects
- Animals, Antibodies, Monoclonal, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, CD4-Positive T-Lymphocytes immunology, Cells, Cultured, DNA-Binding Proteins genetics, GATA3 Transcription Factor, Humans, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, NF-kappa B metabolism, Phenotype, Protein Isoforms genetics, Protein Isoforms metabolism, Receptors, Antigen, T-Cell immunology, Th2 Cells immunology, Trans-Activators metabolism, Transcription, Genetic, CD4-Positive T-Lymphocytes physiology, Cell Differentiation physiology, DNA-Binding Proteins metabolism, Th2 Cells physiology
- Abstract
Schnurri (Shn) is a large zinc finger protein implicated in cell growth, signal transduction, and lymphocyte development. Vertebrates possess at least three Shn orthologues (Shn-1, Shn-2, and Shn-3), which appear to act within the bone morphogenetic protein, transforming growth factor beta, and activin signaling pathways. However, the physiological functions of the Shn proteins remain largely unknown. In Shn-2-deficient mice, mature peripheral T cells exhibited normal anti-T cell receptor-induced proliferation, although there was dramatic enhancement in the differentiation into T helper type (Th)2 cells and a marginal effect on Th1 cell differentiation. Shn-2-deficient developing Th2 cells showed constitutive activation of nuclear factor kappaB (NF-kappaB) and enhanced GATA3 induction. Shn-2 was able to compete with p50 NF-kappaB for binding to a consensus NF-kappaB motif and inhibit NF-kappaB-driven promoter activity. Thus, Shn-2 plays a crucial role in the control of Th2 cell differentiation by regulating NF-kappaB function.
- Published
- 2005
- Full Text
- View/download PDF
41. Differentiation of NK1 and NK2 cells.
- Author
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Kimura MY and Nakayama T
- Subjects
- Animals, Cytokines classification, Humans, Killer Cells, Natural metabolism, Lymphocyte Subsets metabolism, Mice, Cell Differentiation immunology, Cytokines biosynthesis, Killer Cells, Natural cytology, Killer Cells, Natural immunology, Lymphocyte Subsets cytology, Lymphocyte Subsets immunology
- Abstract
Natural killer type-1 (NK1)/NK2 terminology was proposed as an analogy to T helper type-1 (Th1)/Th2 subsets of CD4 T cells. In addition to well recognized IFN-gamma-producing NK1 cells, recent accumulating evidence suggests the presence and the regulatory function of NK2 cells, which produce type-2 cytokines, such as IL-5 and IL-13. Most studies on the production of cytokines by NK1/NK2 subsets have been performed in the human system. Recently, a mouse in vitro NK1/NK2 cell differentiation system was established. A linear 2-0-1 model has been proposed for the differentiation of NK1/NK2 cell subsets, but the branching NK1/NK2 cell differentiation model, comparable to Thl/Th2 cell differentiation, remains a likely explanation. In this review, we summarize the evidence indicating the unique features of NK1/NK2 cells and discuss the above two NK cell differentiation models. In addition, we point to interesting similarities in the expression of transcription factors that regulate cytokine production in NK cells and CD8 T cells.
- Published
- 2005
- Full Text
- View/download PDF
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