Ahmed Kabil, Natalia Nayyar, Chengxi Xu, Julyanne Brassard, Lesley A Hill, Samuel B Shin, Sameeksha Chopra, Bernard Lo, Yicong Li, Mya Bal, Marine Theret, Fabio M V Rossi, T Michael Underhill, Michael R Hughes, Kelly M McNagny
{"title":"Functional targeting of ILC2s and ILC3s reveals selective roles in intestinal fibrosis and homeostasis.","authors":"Ahmed Kabil, Natalia Nayyar, Chengxi Xu, Julyanne Brassard, Lesley A Hill, Samuel B Shin, Sameeksha Chopra, Bernard Lo, Yicong Li, Mya Bal, Marine Theret, Fabio M V Rossi, T Michael Underhill, Michael R Hughes, Kelly M McNagny","doi":"10.1084/jem.20241671","DOIUrl":"10.1084/jem.20241671","url":null,"abstract":"<p><p>Innate lymphoid cells (ILCs) are long-lived, tissue-resident cell analogs to T helper subsets that lack antigen-specific receptors. Understanding the roles of specific ILCs in chronic inflammation and fibrosis has been limited by inadequate tools for selective targeting. Here, we used Il17rb-CreERT2-eGFP and Rorc-Cre strains to selectively delete RORα in ILC2s and ILC3/Th17 cells, respectively. RORα deletion in ILC2s caused significant loss of gastrointestinal ILC2s, increased ILC3 abundance, elevated Th17-type responses, and heightened susceptibility to Crohn's disease-like fibrosis. Conversely, RORα deletion in ILC3/Th17 cells reduced IL-17 production, protecting against fibrosis. Using isolithocholic acid (isoLCA), a microbial secondary bile acid and RORγt inverse agonist, we confirmed the role of ILC3s/Th17 cells in fibrosis. In RORγt reporter and Th17-deficient Rag1-/- mice, isoLCA reduced IL-17 production by ILC3s and attenuated intestinal fibrosis by dampening RORγt-dependent ILC3/Th17 responses. These findings reveal a novel interplay between ILC2s and ILC3s in gut homeostasis and demonstrate the therapeutic potential of targeting RORγt in ILC3s as a strategy for preventing fibrosis.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12118370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159636","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}
Seth D Fortmann, Blake F Frey, Robert F Rosencrans, Yvonne Adu-Rutledge, Edgar Ready V, Kameron V Kilchrist, Robert S Welner, Michael E Boulton, Daniel R Saban, Maria B Grant
{"title":"Prenatally derived macrophages support choroidal health and decline in age-related macular degeneration.","authors":"Seth D Fortmann, Blake F Frey, Robert F Rosencrans, Yvonne Adu-Rutledge, Edgar Ready V, Kameron V Kilchrist, Robert S Welner, Michael E Boulton, Daniel R Saban, Maria B Grant","doi":"10.1084/jem.20242007","DOIUrl":"https://doi.org/10.1084/jem.20242007","url":null,"abstract":"<p><p>Hallmark findings in age-related macular degeneration (AMD) include the accumulation of extracellular lipid and vasodegeneration of the choriocapillaris. Choroidal inflammation has long been associated with AMD, but little is known about the immune landscape of the human choroid. Using 3D multiplex immunofluorescence, single-cell RNA sequencing, and flow cytometry, we unravel the cellular composition and spatial organization of the human choroid and the immune cells within it. We identify two populations of choroidal macrophages with distinct FOLR2 expression that account for the majority of myeloid cells. FOLR2+ macrophages predominate in the nondiseased eye, express lipid-handling machinery, uptake lipoprotein particles, and contain high amounts of lipid. In AMD, FOLR2+ macrophages are decreased in number and exhibit dysfunctional lipoprotein metabolism. In mice, FOLR2+ macrophages are negative for the postnatal fate-reporter Ms4a3, and their depletion causes an accelerated AMD-like phenotype. Our results show that prenatally derived resident macrophages decline in AMD and are implicated in multiple hallmark functions known to be compromised in the disease.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968753","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}
Fanny Saidoune, Danyel Lee, Jeremy Di Domizio, Corentin Le Floc'h, Raphael Jenelten, Jérémie Le Pen, Vincent Bondet, Ana Joncic, Marie-Anne Morren, Vivien Béziat, Shen-Ying Zhang, Emmanuelle Jouanguy, Darragh Duffy, Charles M Rice, Curdin Conrad, Jacques Fellay, Jean-Laurent Casanova, Michel Gilliet, Ahmad Yatim
{"title":"Enhanced TLR7-dependent production of type I interferon by pDCs underlies pandemic chilblains.","authors":"Fanny Saidoune, Danyel Lee, Jeremy Di Domizio, Corentin Le Floc'h, Raphael Jenelten, Jérémie Le Pen, Vincent Bondet, Ana Joncic, Marie-Anne Morren, Vivien Béziat, Shen-Ying Zhang, Emmanuelle Jouanguy, Darragh Duffy, Charles M Rice, Curdin Conrad, Jacques Fellay, Jean-Laurent Casanova, Michel Gilliet, Ahmad Yatim","doi":"10.1084/jem.20231467","DOIUrl":"https://doi.org/10.1084/jem.20231467","url":null,"abstract":"<p><p>Outbreaks of chilblains were reported during the COVID-19 pandemic. Given the essential role of type I interferon (I-IFN) in protective immunity against SARS-CoV-2 and the association of chilblains with inherited type I interferonopathies, we hypothesized that excessive I-IFN responses to SARS-CoV-2 might underlie the occurrence of chilblains in this context. We identified a transient I-IFN signature in chilblain lesions, accompanied by an acral infiltration of activated plasmacytoid dendritic cells (pDCs). Patients with chilblains were otherwise asymptomatic or had mild disease without seroconversion. Their leukocytes produced abnormally high levels of I-IFN upon TLR7 stimulation with agonists or ssRNA viruses-particularly SARS-CoV-2-but not with DNA agonists of TLR9 or the dsDNA virus HSV-1. Moreover, the patients' pDCs displayed cell-intrinsic hyperresponsiveness to TLR7 stimulation regardless of TLR7 levels. Inherited TLR7 or I-IFN deficiency confers a predisposition to life-threatening COVID-19. Conversely, our findings suggest that enhanced TLR7 activity in predisposed individuals could confer innate, pDC-mediated, sterilizing immunity to SARS-CoV-2 infection, with I-IFN-driven chilblains as a trade-off.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002735","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}
Aleksej Frolov, Hao Huang, Dagmar Schütz, Maren Köhne, Nelli Blank-Stein, Collins Osei-Sarpong, Maren Büttner, Tarek Elmzzahi, Mukhran Khundadze, Marina Zahid, Michael Reuter, Matthias Becker, Elena De Domenico, Lorenzo Bonaguro, Axel Kallies, Helen Morrison, Christian A Hübner, Kristian Händler, Ralf Stumm, Elvira Mass, Marc D Beyer
{"title":"Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15.","authors":"Aleksej Frolov, Hao Huang, Dagmar Schütz, Maren Köhne, Nelli Blank-Stein, Collins Osei-Sarpong, Maren Büttner, Tarek Elmzzahi, Mukhran Khundadze, Marina Zahid, Michael Reuter, Matthias Becker, Elena De Domenico, Lorenzo Bonaguro, Axel Kallies, Helen Morrison, Christian A Hübner, Kristian Händler, Ralf Stumm, Elvira Mass, Marc D Beyer","doi":"10.1084/jem.20232357","DOIUrl":"https://doi.org/10.1084/jem.20232357","url":null,"abstract":"<p><p>In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is exacerbated by the prolonged protracted disease course as it complicates the delineation of brain-resident and infiltrating cells. Here, we conducted comprehensive profiling of innate and adaptive immune cells in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia. Using fate-mapping of bone marrow-derived cells, we identified microgliosis accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an expansion of disease-associated microglia (DAM) and effector CD8+ T cells prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells, potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with the recruitment and expansion of T cells as a new characteristic of Spg15-driven neuropathology.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12017274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994661","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":"Role of PRC2 in the stochastic expression of Aire target genes and development of mimetic cells in the thymus.","authors":"Minoru Matsumoto, Masaki Yoshida, Takeshi Oya, Koichi Tsuneyama, Mitsuru Matsumoto, Hideyuki Yoshida","doi":"10.1084/jem.20240817","DOIUrl":"https://doi.org/10.1084/jem.20240817","url":null,"abstract":"<p><p>The transcriptional targets of Aire and the mechanisms controlling their expression in medullary thymic epithelial cells (mTECs) need to be clarified to understand Aire's tolerogenic function. By using a multi-omics single-cell approach coupled with deep scRNA-seq, we examined how Aire controls the transcription of a wide variety of genes in a small fraction of Aire-expressing cells. We found that chromatin repression by PRC2 is an important step for Aire to achieve stochastic gene expression. Aire unleashed the silenced chromatin configuration caused by PRC2, thereby increasing the expression of its functional targets. Besides this preconditioning for Aire's gene induction, we demonstrated that PRC2 also controls the composition of mTECs that mimic the developmental trait of peripheral tissues, i.e., mimetic cells. Of note, this action of PRC2 was independent of Aire and it was more apparent than Aire. Thus, our study uncovered the essential role of polycomb complex for Aire-mediated promiscuous gene expression and the development of mimetic cells.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985788","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}
Nicolas Fonta, Nicolas Page, Bogna Klimek, Margot Piccinno, Giovanni Di Liberto, Sylvain Lemeille, Mario Kreutzfeldt, Anna Lena Kastner, Yusuf I Ertuna, Ilena Vincenti, Ingrid Wagner, Daniel D Pinschewer, Doron Merkler
{"title":"Oligodendrocyte-derived IL-33 regulates self-reactive CD8+ T cells in CNS autoimmunity.","authors":"Nicolas Fonta, Nicolas Page, Bogna Klimek, Margot Piccinno, Giovanni Di Liberto, Sylvain Lemeille, Mario Kreutzfeldt, Anna Lena Kastner, Yusuf I Ertuna, Ilena Vincenti, Ingrid Wagner, Daniel D Pinschewer, Doron Merkler","doi":"10.1084/jem.20241188","DOIUrl":"https://doi.org/10.1084/jem.20241188","url":null,"abstract":"<p><p>In chronic inflammatory disorders of the central nervous system (CNS), tissue-resident self-reactive T cells perpetuate disease. The specific tissue factors governing the persistence and continuous differentiation of these cells remain undefined but could represent attractive therapeutic targets. In a model of chronic CNS autoimmunity, we find that oligodendrocyte-derived IL-33, an alarmin, is key for locally regulating the pathogenicity of self-reactive CD8+ T cells. The selective ablation of IL-33 from neo-self-antigen-expressing oligodendrocytes mitigates CNS disease. In this context, fewer self-reactive CD8+ T cells persist in the inflamed CNS, and the remaining cells are impaired in generating TCF-1low effector cells. Importantly, interventional IL-33 blockade by locally administered somatic gene therapy reduces T cell infiltrates and improves the disease course. Our study identifies oligodendrocyte-derived IL-33 as a druggable tissue factor regulating the differentiation and survival of self-reactive CD8+ T cells in the inflamed CNS. This finding introduces tissue factors as a novel category of immune targets for treating chronic CNS autoimmune diseases.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024202","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}
Artur Stoljar, Maksym Zarodniuk, Rudolf Bichele, Elise Helene Armulik, Uku Haljasorg, Romain Humeau, Marine Besnard, Liis Haljasmägi, Liina Tserel, Merili Peltser, Ahto Salumets, Eliisa Kekäläinen, Kai Kisand, Carole Guillonneau, Martti Laan, Pärt Peterson
{"title":"Impaired Aire-dependent IFN signaling in the thymus precedes the protective autoantibodies to IFNα.","authors":"Artur Stoljar, Maksym Zarodniuk, Rudolf Bichele, Elise Helene Armulik, Uku Haljasorg, Romain Humeau, Marine Besnard, Liis Haljasmägi, Liina Tserel, Merili Peltser, Ahto Salumets, Eliisa Kekäläinen, Kai Kisand, Carole Guillonneau, Martti Laan, Pärt Peterson","doi":"10.1084/jem.20241403","DOIUrl":"https://doi.org/10.1084/jem.20241403","url":null,"abstract":"<p><p>Recent studies have highlighted the role of the thymus in maintaining immune tolerance to type 1 interferons (T1 IFNs). Individuals with thymic abnormalities, such as autoimmune regulator (AIRE) gene mutations, frequently develop neutralizing autoantibodies to interferon-alpha (IFNα). Unlike mice, Aire-deficient rats develop robust autoantibodies to IFNα. Using this rat model, we show that Aire regulates the thymic expression of interferon-stimulated genes (ISGs), which occurs before developing anti-IFNα autoantibodies. In the periphery, we observed a widespread downregulation of ISGs across immune cells and reduced activation of natural killer (NK) cells. Furthermore, the presence of anti-IFNα autoantibodies correlated with reduced peripheral tissue inflammation, suggesting their role in dampening T1 IFN signaling and minimizing tissue infiltration. Our findings reveal that Aire-mediated regulation of thymic T1 IFN signaling is linked to the production of protective anti-IFNα autoantibodies, which inversely correlate with autoimmune pathology in peripheral tissues.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003363","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":"Aging microvasculature: Effects on immune cell trafficking and inflammatory diseases.","authors":"Natalia Reglero-Real, Loïc Rolas, Sussan Nourshargh","doi":"10.1084/jem.20242154","DOIUrl":"10.1084/jem.20242154","url":null,"abstract":"<p><p>Leukocyte recruitment to sites of inflammation is vital for orchestrating an effective immune response. Key to this process is the ability of leukocytes to migrate through venular walls, engaging in sequential interactions with endothelial cells, pericytes, and the venular basement membrane. The aging process exerts profound effects on the molecular and functional properties of the vasculature, thereby influencing the profile and dynamics of leukocyte trafficking during inflammation. In this review, by focusing mainly on neutrophils, we summarize key examples of how the aged microvasculature and perivascular stroma cells promote dysregulated leukocyte-venular wall interactions and present the associated molecular mechanisms. Additionally, we discuss the functional implications of such aberrant leukocyte behavior to age-related and chronic inflammatory pathologies.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199318","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}
Miho Tanaka, Lotus Lum, Kenneth H Hu, Piyush Chaudhary, Savannah Hughes, Cecilia Ledezma-Soto, Bushra Samad, Daphne Superville, Kenneth Ng, Arun Chumber, Ciara Benson, Zoe N Adams, Kelly Kersten, Oscar A Aguilar, Lawrence Fong, Alexis J Combes, Matthew F Krummel, Melissa Q Reeves
{"title":"Tumor cell heterogeneity drives spatial organization of the intratumoral immune response.","authors":"Miho Tanaka, Lotus Lum, Kenneth H Hu, Piyush Chaudhary, Savannah Hughes, Cecilia Ledezma-Soto, Bushra Samad, Daphne Superville, Kenneth Ng, Arun Chumber, Ciara Benson, Zoe N Adams, Kelly Kersten, Oscar A Aguilar, Lawrence Fong, Alexis J Combes, Matthew F Krummel, Melissa Q Reeves","doi":"10.1084/jem.20242282","DOIUrl":"10.1084/jem.20242282","url":null,"abstract":"<p><p>Intratumoral heterogeneity (ITH)-defined as genetic and cellular diversity within a tumor-is linked to failure of immunotherapy and an inferior anti-tumor immune response. We modeled heterogeneous tumors comprised of \"hot\" and \"cold\" tumor populations (giving rise to T cell-rich and T cell-poor tumors, respectively) and introduced fluorescent labels to enable precise spatial tracking. We found the cold tumor cell population exerted a \"dominant cold\" effect in mixed tumors. Strikingly, spatial analysis revealed that the tumor cells themselves created distinct local microenvironments within heterogeneous tumors: regions occupied by cold tumor cells showed pronounced immunosuppression, harboring increased CD206Hi macrophages and diminished local T cell function. This inferior T cell activity in cold regions persisted even after immunotherapy and mechanistically was mediated by CX3CL1 produced by the cold tumor cells. An immune cold tumor population within a heterogeneous tumor thus impairs tumor immunity on both a tumor-wide and a highly localized spatial scale.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 6","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752890","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}
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