Journal of Experimental Medicine最新文献

{"title":"Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.","authors":"Elena Blanco, Carme Camps, Sameer Bahal, Mohit D Kerai, Matteo P Ferla, Adam M Rochussen, Adam E Handel, Zainab M Golwala, Helena Spiridou Goncalves, Susanne Kricke, Fabian Klein, Fang Zhang, Federica Zinghirino, Grace Evans, Thomas M Keane, Sabrina Lizot, Maaike A A Kusters, Mildred A Iro, Sanjay V Patel, Emma C Morris, Siobhan O Burns, Ruth Radcliffe, Pradeep Vasudevan, Arthur Price, Olivia Gillham, Gabriel E Valdebenito, Grant S Stewart, Austen Worth, Stuart P Adams, Michael Duchen, Isabelle André, David J Adams, Giorgia Santili, Kimberly C Gilmour, Georg A Holländer, E Graham Davies, Jenny C Taylor, Gillian M Griffiths, Adrian J Thrasher, Fatima Dhalla, Alexandra Y Kreins","doi":"10.1084/jem.20220979","DOIUrl":"https://doi.org/10.1084/jem.20220979","url":null,"abstract":"<p><p>The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease. Their predominant T cell immunodeficiency is characterized by significant T cell lymphopenia, defects in late stages of thymic T cell development, and impaired function of peripheral T cells, including inadequate NF-κB- and NFAT-mediated, proliferative, and metabolic responses to activation. Pathogenicity is not due to haploinsufficiency, rather ITPR3 protein variants interfere with IP3R channel function leading to depletion of ER Ca2+ stores and blunted SOCE in T cells.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An unconventional purine connection.","authors":"Fabio Grassi","doi":"10.1084/jem.20241527","DOIUrl":"https://doi.org/10.1084/jem.20241527","url":null,"abstract":"<p><p>Xu et al. (https://doi.org/10.1084/jem.20240354) define NAD-induced cell death via purinergic P2RX7 receptor in type 1 unconventional T cells, particularly intrahepatic MAIT cells that are pivotal in liver homeostasis. Therefore, P2RX7 is a potential target to modulate unconventional T cells in immunopathological conditions and cancer.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunomolecular and reactivity landscapes of gut IgA subclasses in homeostasis and inflammatory bowel disease.","authors":"Sonia Tejedor Vaquero, Hadas Neuman, Laura Comerma, Xavi Marcos-Fa, Celia Corral-Vazquez, Mathieu Uzzan, Marc Pybus, Daniel Segura-Garzón, Joana Guerra, Lisa Perruzza, Roser Tachó-Piñot, Jordi Sintes, Adam Rosenstein, Emilie K Grasset, Mar Iglesias, Monica Gonzalez Farré, Joan Lop, Maria Evangelina Patriaca-Amiano, Monica Larrubia-Loring, Pablo Santiago-Diaz, Júlia Perera-Bel, Pau Berenguer-Molins, Monica Martinez Gallo, Andrea Martin-Nalda, Encarna Varela, Marta Garrido-Pontnou, Fabio Grassi, Francisco Guarner, Saurabh Mehandru, Lucia Márquez-Mosquera, Ramit Mehr, Andrea Cerutti, Giuliana Magri","doi":"10.1084/jem.20230079","DOIUrl":"https://doi.org/10.1084/jem.20230079","url":null,"abstract":"<p><p>The human gut includes plasma cells (PCs) expressing immunoglobulin A1 (IgA1) or IgA2, two structurally distinct IgA subclasses with elusive regulation, function, and reactivity. We show here that intestinal IgA1+ and IgA2+ PCs co-emerged early in life, comparably accumulated somatic mutations, and were enriched within short-lived CD19+ and long-lived CD19- PC subsets, respectively. IgA2+ PCs were extensively clonally related to IgA1+ PCs and a subset of them presumably emerged from IgA1+ precursors. Of note, secretory IgA1 (SIgA1) and SIgA2 dually coated a large fraction of mucus-embedded bacteria, including Akkermansia muciniphila. Disruption of homeostasis by inflammatory bowel disease (IBD) was associated with an increase in actively proliferating IgA1+ plasmablasts, a depletion in long-lived IgA2+ PCs, and increased SIgA1+SIgA2+ gut microbiota. Such increase featured enhanced IgA1 reactivity to pathobionts, including Escherichia coli, combined with depletion of beneficial A. muciniphila. Thus, gut IgA1 and IgA2 emerge from clonally related PCs and show unique changes in both frequency and reactivity in IBD.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The protozoan commensal Tritrichomonas musculis is a natural adjuvant for mucosal IgA.","authors":"Eric Yixiao Cao, Kyle Burrows, Pailin Chiaranunt, Ana Popovic, Xueyang Zhou, Cong Xie, Ayushi Thakur, Graham Britton, Matthew Spindler, Louis Ngai, Siu Ling Tai, Dragos Cristian Dasoveanu, Albert Nguyen, Jeremiah J Faith, John Parkinson, Jennifer L Gommerman, Arthur Mortha","doi":"10.1084/jem.20221727","DOIUrl":"10.1084/jem.20221727","url":null,"abstract":"<p><p>Immunoglobulin (Ig) A supports mucosal immune homeostasis and host-microbiota interactions. While commensal bacteria are known for their ability to promote IgA, the role of non-bacterial commensal microbes in the induction of IgA remains elusive. Here, we demonstrate that permanent colonization with the protozoan commensal Tritrichomonas musculis (T.mu) promotes T cell-dependent, IgA class-switch recombination, and intestinal accumulation of IgA-secreting plasma cells (PC). T.mu colonization specifically drives the expansion of T follicular helper cells and a unique ICOS+ non-Tfh cell population, accompanied by an increase in germinal center B cells. Blockade of ICOS:ICOSL co-stimulation or MHCII-expression on B cells is central for the induction of IgA following colonization by T.mu, implicating a previously underappreciated mode of IgA induction following protozoan commensal colonization. Finally, T.mu further improves the induction of IgA-secreting PC specific to orally ingested antigens and their peripheral dissemination, identifying T.mu as a \"natural adjuvant\" for IgA. Collectively, these findings propose a protozoa-driven mode of IgA induction to support intestinal immune homeostasis.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human ITGAV variants are associated with immune dysregulation, brain abnormalities, and colitis.","authors":"Sina Ghasempour, Neil Warner, Rei Guan, Marco M Rodari, Danton Ivanochko, Ryder Whittaker Hawkins, Ashish Marwaha, Jan K Nowak, Yijing Liang, Daniel J Mulder, Lorraine Stallard, Michael Li, Daniel D Yu, Fred G Pluthero, Vritika Batura, Mo Zhao, Iram Siddiqui, Julia E M Upton, Jessie M Hulst, Walter H A Kahr, Roberto Mendoza-Londono, Fabienne Charbit-Henrion, Lies H Hoefsloot, Anis Khiat, Diana Moreira, Eunice Trindade, Maria do Céu Espinheira, Isabel Pinto Pais, Marjolein J A Weerts, Hannie Douben, Daniel Kotlarz, Scott B Snapper, Christoph Klein, James J Dowling, Jean-Philippe Julien, Marieke Joosten, Nadine Cerf-Bensussan, Spencer A Freeman, Marianna Parlato, Tjakko J van Ham, Aleixo M Muise","doi":"10.1084/jem.20240546","DOIUrl":"10.1084/jem.20240546","url":null,"abstract":"<p><p>Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three independent families (two patients and four fetuses) that either caused abnormal mRNA and the loss of functional protein or caused mistargeting of the integrin. This led to eye and brain abnormalities, inflammatory bowel disease, immune dysregulation, and other developmental issues. Mechanistically, the reduction of functional Integrin αV resulted in the dysregulation of several pathways including TGF-β-dependent signaling and αVβ3-regulated immune signaling. These effects were confirmed using immunostaining, RNA sequencing, and functional studies in patient-derived cells. The genetic deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Taken together, the ITGAV variants identified in this report caused a previously unknown human disease characterized by brain and developmental defects in the case of complete loss-of-function and atopy, neurodevelopmental defects, and colitis in cases of incomplete loss-of-function.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MCRS1 sensitizes T cell-dependent immunotherapy by augmenting MHC-I expression in solid tumors.","authors":"Xue Li, Han Yi, Zheyu Jin, Kaitao Jiang, Kangkang Xue, Jin Wang, Yuping Qian, Qian Xiang, Sijing Zhu, Runhe Yan, Yulong Yang, Shenfei Sun, Kai Li, Zichu Zhou, Wei Yu, Ning Jiang, Chen Ding, Xinhua Lin, Jiang Zhong, Yuchao Dong, Yanfang Liu, Xiaofei Yu","doi":"10.1084/jem.20240959","DOIUrl":"10.1084/jem.20240959","url":null,"abstract":"<p><p>Dampened antigen presentation underscores the resistance of pancreatic cancer to T cell-mediated anti-tumor immunity, rendering immunotherapy largely ineffective. By high-throughput CRISPR activation perturbation, we discovered that the transcriptional regulator MCRS1 significantly augmented the sensitivity of mouse pancreatic cancer cells to T cell immunity in vitro and in vivo. Mechanistically, MCRS1 interacted with the transcription factor and genome organizer YY1 to coordinately increase the chromatin accessibility and expression of MHC-I genes. Elevated MCRS1 subverted MHC-I suppression and activated anti-tumor T cells, which sensitized mouse pancreatic cancer to α-PD-1 therapy. Remarkably, high MCRS1 expression was associated with increased T cell infiltration and extended survival of patients with pancreatic cancer and was predictive of favorable responses to α-PD-1 therapy in patients with lung cancer. Together, our study uncovers that MCRS1 sensitizes cancer cells to T cell immunity by transcriptionally subverting MHC-I suppression, which enhances the effectiveness of α-PD-1 therapy in mice and humans, paving the way to further improve immunotherapy against solid tumors.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signaling.","authors":"Calvin Xu, Andreas Obers, Minyi Qin, Alice Brandli, Joelyn Wong, Xin Huang, Allison Clatch, Aly Fayed, Graham Starkey, Rohit D'Costa, Claire L Gordon, Jeffrey Y W Mak, David P Fairlie, Lynette Beattie, Laura K Mackay, Dale I Godfrey, Hui-Fern Koay","doi":"10.1084/jem.20240354","DOIUrl":"https://doi.org/10.1084/jem.20240354","url":null,"abstract":"<p><p>Unconventional T cells, including mucosal-associated invariant T (MAIT), natural killer T (NKT), and gamma-delta T (γδT) cells, comprise distinct T-bet+, IFN-γ+ and RORγt+, IL-17+ subsets which play differential roles in health and disease. NKT1 cells are susceptible to ARTC2-mediated P2X7 receptor (P2RX7) activation, but the effects on other unconventional T-cell types are unknown. Here, we show that MAIT, γδT, and NKT cells express P2RX7 and are sensitive to P2RX7-mediated cell death. Mouse peripheral T-bet+ MAIT1, γδT1, and NKT1 cells, especially in liver, co-express ARTC2 and P2RX7. These markers could be further upregulated upon exposure to retinoic acid. Blocking ARTC2 or inhibiting P2RX7 protected MAIT1, γδT1, and NKT1 cells from cell death, enhanced their survival in vivo, and increased the number of IFN-γ-secreting cells without affecting IL-17 production. Importantly, this revealed the existence of IFN-γ and IL-4 co-producing unconventional T-cell populations normally lost upon isolation due to ARTC2/P2RX7-induced death. Administering extracellular NAD in vivo activated this pathway, depleting P2RX7-sensitive unconventional T cells. Our study reveals ARTC2/P2RX7 as a common regulatory axis modulating the unconventional T-cell compartment, affecting the viability of IFN-γ- and IL-4-producing T cells, offering important insights to facilitate future studies into how these cells can be regulated in health and disease.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Addendum: Resolvins suppress tumor growth and enhance cancer therapy.","authors":"Megan L Sulciner, Charles N Serhan, Molly M Gilligan, Dayna K Mudge, Jaimie Chang, Allison Gartung, Kristen A Lehner, Diane R Bielenberg, Birgitta Schmidt, Jesmond Dalli, Emily R Greene, Yael Gus-Brautbar, Julia Piwowarski, Tadanori Mammoto, David Zurakowski, Mauro Perretti, Vikas P Sukhatme, Arja Kaipainen, Mark W Kieran, Sui Huang, Dipak Panigrahy","doi":"10.1084/jem.2017068101232024a","DOIUrl":"10.1084/jem.2017068101232024a","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 3","pages":""},"PeriodicalIF":15.3,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10829511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD163+ macrophages monitor enhanced permeability at the blood-dorsal root ganglion barrier.","authors":"Harald Lund, Matthew A Hunt, Zerina Kurtović, Katalin Sandor, Paul B Kägy, Noah Fereydouni, Anais Julien, Christian Göritz, Elisa Vazquez-Liebanas, Maarja Andaloussi Mäe, Alexandra Jurczak, Jinming Han, Keying Zhu, Robert A Harris, Jon Lampa, Jonas Heilskov Graversen, Anders Etzerodt, Lisbet Haglund, Tony L Yaksh, Camilla I Svensson","doi":"10.1084/jem.20230675","DOIUrl":"10.1084/jem.20230675","url":null,"abstract":"<p><p>In dorsal root ganglia (DRG), macrophages reside close to sensory neurons and have largely been explored in the context of pain, nerve injury, and repair. However, we discovered that most DRG macrophages interact with and monitor the vasculature by sampling macromolecules from the blood. Characterization of the DRG vasculature revealed a specialized endothelial bed that transformed in molecular, structural, and permeability properties along the arteriovenous axis and was covered by macrophage-interacting pericytes and fibroblasts. Macrophage phagocytosis spatially aligned with peak endothelial permeability, a process regulated by enhanced caveolar transcytosis in endothelial cells. Profiling the DRG immune landscape revealed two subsets of perivascular macrophages with distinct transcriptome, turnover, and function. CD163+ macrophages self-maintained locally, specifically participated in vasculature monitoring, displayed distinct responses during peripheral inflammation, and were conserved in mouse and man. Our work provides a molecular explanation for the permeability of the blood-DRG barrier and identifies an unappreciated role of macrophages as integral components of the DRG-neurovascular unit.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 2","pages":""},"PeriodicalIF":15.3,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10733632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138804840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Landscape of mast cell populations across organs in mice and humans.","authors":"Marie Tauber, Lilian Basso, Jeremy Martin, Luciana Bostan, Marlene Magalhaes Pinto, Guilhem R Thierry, Raïssa Houmadi, Nadine Serhan, Alexia Loste, Camille Blériot, Jasper B J Kamphuis, Mirjana Grujic, Lena Kjellén, Gunnar Pejler, Carle Paul, Xinzhong Dong, Stephen J Galli, Laurent L Reber, Florent Ginhoux, Marc Bajenoff, Rebecca Gentek, Nicolas Gaudenzio","doi":"10.1084/jem.2023057001172024c","DOIUrl":"10.1084/jem.2023057001172024c","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 2","pages":""},"PeriodicalIF":15.3,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10818104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139542391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}