SPEAKERS
of the webinar series
James Di Santo received a combined MD/PhD from Cornell Medical College and the Sloan Kettering Institute in NYC, pursued postdoctoral training with Pr Alain Fischer (Necker Hospital, Paris) and Pr Klaus Rajewsky (Institute for Genetics, Cologne) before creating his own laboratory in 1999 at the Institut Pasteur in Paris, France. He currently holds the position of Professor in the Immunology Department at Institut Pasteur and Director of Research within the French Medical Research Institute (Inserm) and leads the Innate Immunity Unit and the Inserm Unit 1223. Pr. Di Santo’s scientific interests include the role for instrinsic and environmental signals in the development and function of both adaptive (T and B cell) and innate lymphoid cells (ILC, NK cells) in mice and man. In parallel, Pr. Di Santo has developed a series of humanized mouse models for the immune system that allows fundamental questions in human immunology (especially in relation to infectious diseases) to be addressed. Recently, he has developed an integrated systems immunology approach using nasal swab samples to assess mucosal immunity in healthy individuals and patients suffering from respiratory diseases. These projects align to develop novel immunological approaches to treat chronic as well as emerging infectious diseases of global health interest.
Innate lymphoid cells: development, differentiation, dynamics
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Innate lymphoid cells (ILCs) are a family of specialized immune cells that differentiate from hematopoietic precursors into canonical groups (ILC1, ILC2, ILC3) that can rapidly provide critical soluble cytokines in the context of infection and inflammation. ILCs have the potential to sense environmental changes within tissues which can imprint changes in their effector functions: this can result in durable reinforced capacities (‘training’ and ‘fitness’) or new functionalities (‘plasticity’). The mechanistic underpinning of these environmentally induced changes in ILC function are unclear but the re-wiring of metabolic pathways is likely to be involved. How ILCs physically behave as long-lived tissue-resident cells is likewise poorly understood. Here I will described recent and ongoing studies to understand the impact of intestinal ILC heterogeneity and cellular dynamics for mucosal barrier function in health and disease.
Sidonia Fagarasan completed training in clinical medicine at Iuliu Hatieganu University of Medicine and Pharmacy in 1990. She did residency and speciality in the Clinical Laboratory for Microbiology, Biochemistry and Hematology at the University of Medicine and Pharmacy, Cluj-Napoca, and was appointed to Assistant Professor in 1995. It was during this clinical period in Romania that she developed a fascination into the mechanisms governing intestinal immune homeostasis. In 1998, she was invited to Japan as a Mombusho Visiting Researcher and earned PhD from Kyoto University Faculty of Medicine in 2000. In Kyoto, she contributed to the discovery of Activated Induced Deaminase (AID) with Tasuku Honjo and colleagues. She subsequently demonstrated the critical role of AID in gut homeostasis and the critical role of Immunoglobulin (Ig)A selection for regulating microbial communities in the gut. She was appointed as Team Leader of the Laboratory for Mucosal Immunity at the Research Center for Allergy and Immunology (RCAI) in 2002. Since 2013, she has been Team Leader of Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences (IMS). Her group discovered the adaptive regulatory pathways modulating the IgA production and body
The intersection of adaptive and innate immunity in the lung: implications for chronic pulmonary insufficiency
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Satomi Ito1, Baihao Zhang1, Seiko Narushima1, Yuki Sugiura2 and Sidonia Fagarasan1,3
1Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Japan – 2Multiomics Platform, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan – 3Division of Integrated High-Order Regulatory Systems, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
Immunodeficiencies of adaptive immune system are frequently implicated in recurrent infections and dysfunction of multiple organs, including the lung. However, much remains unknown in respect to immunological interactive networks and the immune cells modulation of local pulmonary barrier, including epithelial and endothelial cells.
We observed that adult mice deficient in T cells, spontaneously develop chronic inflammatory lung diseases characterized by leukocytes infiltration, fibrosis and alveolar proteinosis. Using single-cell transcriptome analyses, we reveal considerable changes in the cell composition and identify two unique myeloid subpopulations in T cell-deficient mice: the CD14+ inflammatory monocytes and the alveolar CD1d+ foamy macrophages, which are associated with pulmonary inflammation and alveolar proteinosis.
Metabolomic analysis of bronchoalveolar lavage fluid (BALF) and interstitial lung tissues, revealed a biochemical reconfiguration especially in lipids and tryptophan metabolism pathways.
I will discuss how tryptophan derived metabolites produced by activated B cells contribute to generation of foamy macrophages and disruption of epithelial and endothelial barrier integrity.
Kenji Kabashima graduated from Kyoto University in 1996. He trained in Medicine and Dermatology at the United States Naval Hospital in Yokosuka, Japan, Kyoto University Hospital, and the University of Washington Medical Center in the USA. His research on bioactive lipid mediators at Kyoto University culminated in a PhD under the supervision of Professor Shuh Narumiya. He furthered his studies in the Department of Dermatology at Kyoto University Graduate School of Medicine (under Professor Yoshiki Miyachi), UCSF (under Professor Jason Cyster), and the University of Occupational and Environmental Health (under Professor Yoshiki Tokura).
Currently, he is a chair and professor at the Department of Dermatology, Kyoto University Graduate School of Medicine, Japan. Additionally, he is a principal investigator at SRIS/A*STAR in Singapore and a visiting consultant at the National Skin Centre in Singapore. His primary research interests include the mechanisms of inflammatory skin diseases (such as atopic dermatitis, contact dermatitis, and psoriasis) in both mice and humans and the 3D visualization of the skin using two-photon microscopy.
His hobbies include marathons (his personal best is 2:54:38), trail running (Ultra Trail du Mont Blanc 170 km), golf, climbing, and traveling.
Newly identification of CXCR6+ resident memory CD4+ T cells in allergic skin diseases
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CD4+ tissue-resident memory T (TRM) cells, persisting in the skin post-allergic reactions, rapidly incite inflammation upon antigen reencounter. The sustenance and functional diversity of these cells, however, are not fully elucidated. In our study, we utilized a delayed-type hypersensitivity model, transferring ovalbumin (OVA)-specific CD4+ T cells into T cell receptor-β deficient mice. Following sensitization with OVA emulsion and ear skin challenge, CD4+ T cells with a CD44+CD69+ TRM phenotype remained in the dermis even after ear swelling subsided on day 35. Parabiosis experiments corroborated their tissue residency. Immunohistochemical analyses demonstrated clustering of CD4+ TRM cells with CD301b+ dermal dendritic cells. Investigating this interaction further, selective depletion of CD301b+ cells in CD301b-diphtheria toxin receptor mice led to a marked reduction in CD4+ TRM cell clusters and numbers. Concurrently, transcription levels of CXC-chemokine ligand 16 (CXCL16) diminished. Its receptor, CXC-chemokine receptor 6 (CXCR6), was predominantly expressed on CD4+ TRM cells. Blocking CXCL16 curtailed the proliferation of CXCR6+CD4+ TRM cells and mitigated rapid ear swelling upon re-challenge. RNA sequencing revealed that upon re-challenge, CXCR6+CD4+ TRM cells secreted IFN-γ and IL-13, while CXCR6-CD4+ TRM cells exhibited a Foxp3+ regulatory T cell phenotype. These findings illuminate the pivotal role of CXCR6+CD4+ TRM cells in pathogenesis during recall responses via effector cytokines, sustained by interactions with CD301b+ dendritic cells through CXCL16. This elucidation offers novel avenues for preventing recurrent chronic allergic skin disorders, such as atopic dermatitis.
Professor Rachel Golub stands at the forefront of immunological research as the leader of the “Development of Innate Lymphoid Cells (ILC) and Inflammation” research group at the Institut Pasteur. With a career dedicated to unraveling the complexities of the immune system, her pioneering work has advanced our understanding of hematopoiesis. Her contributions to the field began with her insightful characterization of the fetal compartment of hematopoietic stem cells and the mechanisms of hematopoiesis within the fetal spleen. These early discoveries laid the foundation for her subsequent research endeavors, which have increasingly focused on the biology of ILCs. Prof. Golub’s research has been instrumental in underlining the pivotal functions of the Notch signaling pathway in the differentiation of clonal ILC precursors during both fetal and adult life. This work not only deepens our comprehension of the developmental pathways of immune cells but also highlights the plasticity and adaptability of the immune system in response to environmental cues. At the heart of Prof. Golub’s scientific inquiry is her dedication to exploring how inflammation influences the development, fate, and functionality of ILCs. Her team’s current projects are exploring the critical roles that ILC populations play in a range of pathologies, including non-alcoholic steatohepatitis.
Enhanced NK cell-poiesis in metabolic-dysfunction-associated steatohepatitis
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Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by lipid accumulation and insulin resistance, explained by the "multiple hit" hypothesis. Factors such as lifestyle, the gut microbiome, dietary habits, and obesity play significant roles. These conditions lead to changes in the gut microbiota, which increase hepatic lipogenesis and decrease the inhibition of lipolysis in adipose tissue. This results in an excess of free fatty acids in the liver and subsequent fat accumulation. The accumulated fat causes lipotoxicity, impairing mitochondrial function and leading to the production of reactive oxygen species and stress on the endoplasmic reticulum. Coupled with insulin resistance, this condition also increases the absorption of lipopolysaccharides (LPS) from the gut due to enhanced intestinal permeability associated with an altered gut microbiome. The resulting cellular damage triggers immune cell infiltration, inflammation, and fibrogenesis. MASH is increasingly becoming a primary cause of hepatocellular carcinoma (HCC) development. The role of NK cells in MASH remains a topic of debate, as their impact on disease progression may be both protective and harmful. NK cells develop in the bone marrow (BM), where they mature and acquire functional capabilities before dispersing to various tissues, including the liver, where they are the predominant population of lymphocytes. Using induced MASH models through two different diets, we observed an increase in the frequency and numbers of specific hepatic NK subsets, characterized by "immature" and activated markers, along with a significant increase in IFNγ secretion. We have identified the molecular mechanisms behind liver NK cell recruitment and accumulation in MASH. We propose a cellular dialogue between BM monocytes and NK precursors involving the IL-15 and osteopontin pathways, partially driven by endotoxemia. This tripartite gut-liver-BM axis regulates the influx of innate immune populations recruited to the liver, impacting disease progression.
Dr. Molly Ingersoll received her PhD studying host-pathogen interactions from NYU School of Medicine working with Arturo Zychlinsky at NYU and at the Max Planck Institute for Infection Biology in Berlin, Germany. A brief postdoctoral fellowship at Washington University School of Medicine, in St Louis, MO with Scott Hultgren, studying innate immunity to urinary tract infection was followed by a postdoctoral appointment at Mount Sinai Medical Center in NYC, investigating monocyte and dendritic cell biology. Dr. Ingersoll is a Research Director with joint appointment between Institut Cochin and Institut Pasteur in Paris. Her team studies mucosal immunity in the bladder in the context of infection and cancer – to understand how this tissue responds to infectious and non-infection inflammatory diseases and to develop immunomodulatory approaches to improve disease outcomes.
Mucosal immunity in the bladder
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Urinary tract infections (UTI) are the second most common infection, impacting nearly 50% of all women. Indeed, otherwise healthy, premenopausal women have a significantly greater incidence of urinary tract infection (UTI) than men, yet, conversely, male UTI is more persistent with greater associated morbidity. Additionally, both sexes are at significant risk of reinfection, suggesting that adaptive immune responses to this infection are insufficient. Our group is interested in identifying the mechanisms that govern sex bias and development of immunity in UTI. Our recent work demonstrates that resident macrophages impair the adaptive response, and that IL-17 is a critical player in resolution of infection. We also identified events leading to the development of antigen-specific tissue-resident T cells in the bladder that are necessary and sufficient for protection against recurrent infection. We are now determining how this response can be immunomodulated for improved therapeutics that obviate the need for antibiotics to treat multidrug resistant uropathogens.
Tomohiro Kurosaki received his M.D. in 1980 from Okayama University Medical School and his Ph.D. in molecular biology and biochemistry from Kyoto University in 1987. Soon he joined Dr. Jeffrey Ravetch’s Laboratory as his first Japanese postdoctoral fellow at the Sloan-Kettering Institute in New York. In 1992, he moved to Lederle Laboratories and worked until 1996 as an independent research scientist, while holding the position of adjunct assistant professor in Yale University in the United States. After returning to Japan, he directed his own laboratory and taught at the Institute for Liver Research at Kansai Medical University. He joined RIKEN in 2001 and has been a group director of his own research group. In 2008, he also joined Osaka University and became a specially appointed professor in WPI Immunology Frontier Research Center. Since then, he has been running two laboratories. In April 2024, RIKEN became his primary affiliation again, while maintaining his laboratory in Osaka University as a visiting professor. His major contribution to the field is dissecting BCR signaling and elucidating memory B cell function.
Functions of two humoral memory populations and their generation mechanisms
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The successful establishment of humoral memory response depends on at least two layers of defense. Pre-existing protective antibodies secreted by long-lived plasma cells (LLPCs) act as a first line of defense against reinfection (“constitutive humoral memory”). Previously, a second line of defense in which pathogen-experienced memory B cells are rapidly reactivated to produce antibodies (“reactive humoral memory”), was considered as simply a back-up system for the first line (particularly for re-infection with homologous viruses). By using influenza model system, we found that, in the case of re-infection with similar but different strains of viruses, the constitutive humoral memory (LLPCs) is no more protective, while reactive humoral memory (memory B cells) plays a crucial role. These somewhat differential roles of LLPCs and memory B cells promoted us to look for the generation mechanisms of the two compartments in germinal centers (GCs). We proposed the affinity instruction model, whereby a high-affinity or low-affinity BCR is the primary determinant for LLPC or memory B cell generation, respectively. I will present the experimental data to support this model.
After receiving his PhD in Immunology at Centre d’Immunologie de Marseille-Luminy (CIML) on the functional characterization of the human T cell clones, Bernard Malissen spent two years as a Visiting Associate at the California Institute of Technology (Caltech), and then became a team leader at CIML. He pioneered in the eighties the use of gene transfer approaches to dissect the function of molecules involved in T cell function (MHC, TCR and coreceptors).
He also elucidated the atomic structure of several TCR in complex with peptide- MHC ligand, providing explanation for TCR cross-reactivity and alloreactivity. In the late eighties, the possibility to edit the mouse genome “à la carte” led him to develop innovative mouse models allowing to tackle the function of T cells, macrophages, and dendritic cells in their in vivo physiological context. To make sense of the formidable complexity of the signal transduction networks involved in T cell activation, his teams at CIML and Center for Immunophenomics (CIPHE) combine mouse functional genomics and high-throughput “omic” approaches to further the understanding of T cell function under normal and pathological conditions.
Unveiling the molecular basis of T cell malfunctions and disorders using multi-omics approaches
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T cells play a central role in adaptive immunity. Although the T cell antigen receptor (TCR) primarily controls T cell physiology, it does not work in isolation and the signals it triggers are tuned by a multitude of other surface receptors that deliver positive (costimulators) and negative (coinhibitors) informations about the state of activation of antigen-presenting cells (primarily dendritic cells). Therapeutic antibodies (immune-checkpoint inhibitors) blocking coinhibitors have become standard treatment for several malignant conditions, leading to a revival in the study of T cell coinhibition and costimulation. However, we lack a satisfying comprehension of the way T cells integrate inputs from multiple signalling pathways and use inter-pathway crosstalk to make informed decisions. To make sense of the formidable complexity of the signal transduction networks involved in T cell activation and the role played by the different types of dendritic cells in T cell activation, we combined “omic” and mouse genetics. It allowed us to decipher in a time-resolved and quantitative manner the dynamics of the protein signaling complexes (signalosomes) that assemble in primary T cells following physiologic TCR engagement. To further illustrate the interest of multi-omics approaches, I will present recent data generated with several Japanese collaborators and demonstrating how corrupted LAT signalosomes lead to an inflammatory and autoimmune disease recapitulating human IgG4-related disease.
Dr. Kazuyo Moro graduated from Nihon University School of Dentistry in 2003 and obtained her Ph.D. in the Department of Microbiology and Immunology at Keio University School of Medicine in 2010. In 2012, she joined RIKEN as a senior researcher and later became the team leader for the Laboratory for Innate Immune Systems in 2015. Additionally, she serves as a professor in the Department of Microbiology and Immunobiology at the Graduate School of Medicine, Osaka University since 2019.
Her research focuses on group 2 innate lymphoid cells (ILC2s), a discovery she made in 2010. Her research extends to the cytokine regulation and development of ILC2s, exploring their roles in allergic diseases, fibrosis, endometriosis, inflammatory bowel disease, and the aging process. Her overarching goal is to achieve a comprehensive understanding of ILC2-related diseases and their impact on human health.
Activation of ILC2s through constitutive IFNγ signaling reduction leads to spontaneous pulmonary fibrosis
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Pulmonary fibrosis (PF) is characterized by inflammation and collagen deposition in the alveolar interstitium, resulting in dyspnea and death. Patients with PF often exhibit decreased levels of IFNγ, leading to fibroblast proliferation and collagen synthesis. Our study using Ifngr1-/-Rag2-/- mice, which lack mechanisms to suppress ILC2s and ILC3s, revealed spontaneous and severe PF development. Levels of surfactant protein D (SP-D), a common clinical biomarker reflecting disease activity, increased and the saturation of percutaneous oxygen (SpO2) levels significantly decreased in aged mice. In these mice, the IL-33hiIL-13hi ILC2 subpopulation increased during the disease-onset phase before collagen production commenced. Because fibrosis disappears in ILC-deficient or IL-33-deficient mice, IL-33-mediated activation of ILC2s seems to be critical for fibrosis. ILC2s were found to directly induce collagen production by fibroblasts in vitro, and pathogenic fibroblasts began producing IL-33 in the chronic phase, presumably establishing a positive feedback loop between fibroblasts and ILC2s leading to irreversible fibrosis. Finally, the increased expression of IL1RL1 (IL-33R) and IL13, along with decreased expression of IFNGR1 were confirmed in ILC2s from idiopathic pulmonary fibrosis patients, suggesting that dysregulation of ILC2s may also cause endogenous fibrosis in humans.
In this seminar, I'll discuss current research that focuses on how ILC3 and neutrophils contribute to the sustained activation of ILC2 through IL-33 in the context of PF.
D. Olive, after a training in Internal Medicine, he is currently Professor of Immunology at Aix Marseille University and Institut Paoli Calmettes, he is also in charge of the « Immunity and Cancer » research team of INSERM UMR1068 of Marseille Cancer Research Center . He is the head of the first IBiSA Platform dedicated to Cancer Immunomonitoring Platform.
Olive has been a pioneer and leader in the co-signalling field since 1990. His work is dedicated to tumor immunology with a major emphasis on innate immunity and co-signalling molecules.
Selected major breakthroughs:
1) Identification of signaling pathways involved in CD28 and ICOS costimulatory molecules; 2) First to demonstrate that BTN3A1/CD277 is a major inducer of Vg9Vd2 response; 3) First to demonstrate the recognition of AML by Vg9Vd2 ; 4) identification of the function of BTLA and HVEM in the regulation of immune function; 4) identification of HVEM and BTLA as escape mechanisms in melanoma and non hodgkin lymphoma; 5) Identification of molecular mechanisms associated to NK cells impairment in AML patients; 6) first identification of alteration of NK cells in the tumor bed in breast cancer; 7) First in man clinical trial using anti-KIR and anti-BTN3A mAbs in AML patients; 8) demonstration of the targeting of pDC by HCV; 9) Deciphering of of ICOS ICOSL interaction in the regulation of Tregs in non Hodgkin lymphomas and in the targeting of CTCL.
He is actively involved in translating discoveries to Biotech that he has either co-founded (Imcheck Therapeutics, Emergence Therapeutics , Alderaan Biotechnology, Stealth IO) as well as out-licensing patents to pharmas (ICOS to GSK, anti-CD28 to Ose Immunotherapeutics and Asahi Kasei , anti-Nectin-4 to Emergence Therapeutics-Ely Lily and BTN3A to Imcheck Therapeutics that are currently in clinical trial).
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In contrast to αβ T cells, γδ T cell activation is MHC-unrestricted and relies on the detection of various host cell-derived molecules or exogenous pathogens by both TCR and non-TCR receptors. γδ T cells represent the earliest source of IFNγ secretion in the tumor microenvironment and recent transcriptome analyses of human tumors reveal that high γδ T infiltration has the best prognostic value in comparison to other immune subsets. Vγ9Vδ2 T cells are the major subtype of blood γδ T cells and are activated by non-peptidic phosphorylated metabolites, called phosphoantigens (pAgs), produced by transformed or infected cells.
During this presentation we will address 1) the role of these cells as prognostic markers in various hematological and solid tumors ; 2) their mechanismm of action against tumors ; 3) clinical trials in solid tumors and leukemias.
Dr. E. Piaggio obtained the diploma of clinical biologist and the PhD in Immunology at the National University of Rosario, Argentine. She did her post-doctoral studies in France and is research director of INSERM. She directs the “Translational Immunotherapy team” at Institut Curie, in Paris. Her team is part of the first French Center for Cancer Immunotherapy. Her main contributions have been in the field of regulatory T-cell based immunotherapy of infectious diseases (Chagas’ disease), autoimmunity (type 1 diabetes and multiple sclerosis/EAE), alloreactivity (GVHD and transplantation) and more recently, cancer; including Ab-based and Il-2-based therapies. She is co-founder of Egle-Therapeutics, a biotech developing Treg-based immunotherapies.
Regulatory T cells and cancer: a translational approach
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Dr Piaggio will present recent results on the identification of Functional Tumor-Associated Treg targets using scRNA, scTCR and scATAC sequencing technologies. From target discovery to clinical application. Additionally, fundamental new data on the biology of follicular Tregs will be discussed.
Naoko Satoh-Takayama obtained her Ph.D. from The University of Tokyo in 2007. Immediately after graduation, she started her career as a postdoctoral fellow (Prof. James Di Santo) at the Institut Pasteur in France, supported by a grant from the French government. In 2008, she identified and reported a novel cell subset, currently termed group 3 innate lymphoid cells (ILC3). In 2011, she became a Chargé de Recherche at the Institut Pasteur. She then moved back to Japan and joined Dr. Hiroshi Ohno’s group at IMS, RIKEN as a permanent researcher in 2015. She was promoted to Senior Research Scientist in 2019. Since 2024, she has been the leader of the Precision Immune Regulation RIKEN ECL Research Unit to investigate the important role of immune responses in disease regulation, with a particular focus on innate lymphoid cells.
Commensal-derived metabolites induce IL-33 production from fibroblasts and activate stomach ILC2s for mucosal protection
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Immune responses in mucosal organs are regulated by specific microbes. ILC2s contribute to the initiation of immune responses against pathogenic infections in the stomach. However, the role of commensal bacteria in controlling ILC2s to promote gastric immunity remains unclear. Here, we report that the commensal bacterium YL27, recently proposed as a member of the Muribaculaceae, impacts stomach ILC2s via IL-33-producing Sca1+Ly6C+CD140a+ fibroblasts and induces their effector functions via IL-13. IL-33 production by fibroblasts was induced by acetate, a metabolite of YL27, via its receptor GPR43. Furthermore, preferential IL-13 from stomach-ILC2s activated by IL-33-producing fibroblasts was involved in stomach protection by upregulating mucin production to maintain stomach homeostasis. We further demonstrated that ILC2s activated by commensal YL27 induce IgA production leading to elimination of the pathogenic bacterium H. pylori via cross-reactive binding. Our study thus indicates that the stomach exhibits a flexible response to pathogenic or commensal bacteria through different sources of IL-33 for ILC2s activation, making it the first line of defense against the invasion of a wide variety of foreign antigens via unique immunological mechanisms.
Osamu Takeuchi received his M.D. from Osaka University Medical School (Suita, Japan) in 1995. After clinical training, he entered the graduate school of medicine at Osaka University, where he began researching innate immunity under Prof. Shizuo Akira. He discovered that different Toll-like receptors (TLRs) recognize various microbial components and earned his Ph.D. He then completed postdoctoral training at Dana-Farber Cancer Institute under Prof. Stanley Korsmeyer. Following this, he became an assistant professor at Osaka University, focusing on the functional roles of TLR signaling molecules and RIG-I-like receptors in inflammation. In 2012, he joined the Institute for Frontier Life and Medical Sciences at Kyoto University as a full professor, and in 2018, he moved to the Graduate School of Medicine. His current research focuses on the post-transcriptional regulation of immune and inflammatory responses with an emphasis on innate immunity.
Post-transcriptional regulation of inflammation: Regnase-1 as a key “brake” of immune responses
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Post-transcriptional regulation is critical for the control of immune cell activation. Regnase-1 is an RNA-binding proteins (RBPs) and acts as an endoribonuclease that degrades inflammatory mRNAs by recognizing stem-loop (SL) structures in the 3' untranslated regions (3'UTRs). Dysregulated expression of Regnase-1 is associated with the pathogenesis of inflammatory and autoimmune diseases in mice and human. Regnase-1 is involved in a variety of human diseases including ulcerative colitis, multiple sclerosis and pulmonary hypertension. The expression of Regnase-1 is maintained by self-regulation degrading its own mRNA. We developed a therapeutic strategy to suppress inflammatory responses by blocking Regnase-1 self-regulation, which was mediated by the simultaneous use of two antisense-oligonucleotides (ASOs) to alter the binding of Regnase-1 toward the SL structures in its 3' UTR. Regnase-1-targeting ASOs not only enhanced Regnase-1 expression but also effectively reduced the expression of multiple proinflammatory transcripts in macrophages. Administration of Regnase-1-targeting ASOs ameliorated acute respiratory inflammation and encephalitis mouse models. Collectively, ASO-mediated disruption of the Regnase-1 self-regulation pathway is a potential therapeutic strategy to enhance Regnase-1 abundance, which, in turn, provides therapeutic benefits for treating inflammatory diseases by suppressing inflammation. Regnase-3, a Regnase-1-related protein, and Regnase-1 function in hematopoietic stem and progenitor cells (HSPCs) for the determination of myeloid and lymphoid lineages by degrading Nfkbiz mRNA. An ASO designed to inhibit SL structures in Nfkbiz 3' UTR successfully augmented Nfkbiz expression and facilitated myelopoiesis. Taken together, ASO-mediated inhibition of mRNA degradation via Regnsae-1-related endoribonucleases is a prominent strategy to control immune responses.