Journal of Experimental Medicine最新文献_第6页

Correction: Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. 更正：线粒体自噬介导的脂肪炎症有助于2型糖尿病伴肝脏胰岛素抵抗。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-06-13 DOI: 10.1084/jem.2020141606022025c

Feng He, Yanrui Huang, Zhi Song, Huanjiao Jenny Zhou, Haifeng Zhang, Rachel J Perry, Gerald I Shulman, Wang Min

引用次数: 0

Role of PRC2 in the stochastic expression of Aire target genes and development of mimetic cells in the thymus. PRC2在胸腺Aire靶基因的随机表达和模拟细胞发育中的作用。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-04-17 DOI: 10.1084/jem.20240817

Minoru Matsumoto, Masaki Yoshida, Takeshi Oya, Koichi Tsuneyama, Mitsuru Matsumoto, Hideyuki Yoshida

{"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":"10.1084/jem.20240817","url":null,"abstract":"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.","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}

引用次数: 0

Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15. 小胶质细胞和CD8+ T细胞激活在小鼠痉挛性截瘫模型中的神经元丢失之前15。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-04-23 DOI: 10.1084/jem.20232357

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":"10.1084/jem.20232357","url":null,"abstract":"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.","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}

引用次数: 0

Impaired Aire-dependent IFN signaling in the thymus precedes the protective autoantibodies to IFNα. 胸腺中空气依赖性IFN信号的受损先于对IFNα的保护性自身抗体。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-04-30 DOI: 10.1084/jem.20241403

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":"10.1084/jem.20241403","url":null,"abstract":"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.","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}

引用次数: 0

Oligodendrocyte-derived IL-33 regulates self-reactive CD8+ T cells in CNS autoimmunity. 少突胶质细胞来源的IL-33在中枢神经系统自身免疫中调节自身反应性CD8+ T细胞。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-04-14 DOI: 10.1084/jem.20241188

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":"10.1084/jem.20241188","url":null,"abstract":"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.","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}

引用次数: 0

Aging microvasculature: Effects on immune cell trafficking and inflammatory diseases. 衰老微血管：对免疫细胞运输和炎症性疾病的影响。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-06-02 DOI: 10.1084/jem.20242154

Natalia Reglero-Real, Loïc Rolas, Sussan Nourshargh

引用次数: 0

Correction: Transcription of HIV-1 at sites of intact latent provirus integration. 更正：HIV-1在完整潜伏前病毒整合位点的转录。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-06-02 Epub Date: 2025-05-23 DOI: 10.1084/jem.2024039105162025c

Ana Rafaela Teixeira, Cintia Bittar, Gabriela S Silva Santos, Thiago Y Oliveira, Amy S Huang, Noemi Linden, Isabella A T M Ferreira, Tetyana Murdza, Frauke Muecksch, R Brad Jones, Marina Caskey, Mila Jankovic, Michel C Nussenzweig

引用次数: 0

Tumor cell heterogeneity drives spatial organization of the intratumoral immune response. 肿瘤细胞异质性驱动肿瘤内免疫反应的空间组织。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-06-02 Epub Date: 2025-04-01 DOI: 10.1084/jem.20242282

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":"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.","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}

引用次数: 0

Breast cancer gene-1 (BRCA1) potentiates maladaptive repair after kidney injury. 乳腺癌基因1 （BRCA1）增强肾损伤后的不适应修复。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-06-02 Epub Date: 2025-03-28 DOI: 10.1084/jem.20231107

Amrendra K Ajay, Akinwande A Akinfolarin, Cody C Gifford, Venkata S Sabbisetti, Joseph V Bonventre

{"title":"Breast cancer gene-1 (BRCA1) potentiates maladaptive repair after kidney injury.","authors":"Amrendra K Ajay, Akinwande A Akinfolarin, Cody C Gifford, Venkata S Sabbisetti, Joseph V Bonventre","doi":"10.1084/jem.20231107","DOIUrl":"10.1084/jem.20231107","url":null,"abstract":"Maladaptive repair following kidney tubular injury leads to the development of interstitial fibrosis, a pathology common to chronic kidney diseases (CKD). Dysfunctional DNA damage response plays an important role in the progression of CKD. We found that BRCA1 expression was increased in the kidneys of patients with CKD and fibrotic kidneys of mice. Exon 11 deletion of Brca1 in proximal tubule cells (PTCs) of mice subjected to ischemic or nephrotoxic (aristolochic acid) injury resulted in a reduced number of senescent cells, as assessed by a decrease in phospho-histone H3, p16INK4a, RAD51 recruitment, G2/M cell cycle phase cells, GATA4, and senescence-associated β-galactosidase. There was less production of inflammatory profibrotic mediators and reduced kidney fibrosis. After cisplatin exposure in vitro, human PTCs with reduced BRCA1 had increased apoptosis, decreased RAD51 nuclear foci, and fewer cells in the G2/M cell cycle phase, with reduced IL-6 and sonic hedgehog production. Thus, BRCA1 regulates nonmalignant tissue responses to kidney injury, a role hitherto unrecognized.","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/PMC11951932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728755","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}

引用次数: 0

Age- and diet-instructed metabolic rewiring of the tumor-immune microenvironment. 年龄和饮食指示的肿瘤免疫微环境的代谢重新布线。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-06-02 Epub Date: 2025-04-11 DOI: 10.1084/jem.20241102

Ana Belén Plata-Gómez, Ping-Chih Ho

{"title":"Age- and diet-instructed metabolic rewiring of the tumor-immune microenvironment.","authors":"Ana Belén Plata-Gómez, Ping-Chih Ho","doi":"10.1084/jem.20241102","DOIUrl":"https://doi.org/10.1084/jem.20241102","url":null,"abstract":"The tumor-immune microenvironment (TIME) plays a critical role in tumor development and metastasis, as it influences the evolution of tumor cells and fosters an immunosuppressive state by intervening the metabolic reprogramming of infiltrating immune cells. Aging and diet significantly impact the metabolic reprogramming of the TIME, contributing to cancer progression and immune evasion. With aging, immune cell function declines, leading to a proinflammatory state and metabolic alterations such as increased oxidative stress and mitochondrial dysfunction, which compromise antitumor immunity. Similarly, dietary factors, particularly high-fat and high-sugar diets, promote metabolic shifts, creating a permissive TIME by fostering tumor-supportive immune cell phenotypes while impairing the tumoricidal activity of immune cells. In contrast, dietary restrictions have been shown to restore immune function by modulating metabolism and enhancing antitumor immune responses. Here, we discuss the intricate interplay between aging, diet, and metabolic reprogramming in shaping the TIME, with a particular focus on T cells, and highlight therapeutic strategies targeting these pathways to empower antitumor immunity.","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/PMC11987706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021144","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}

引用次数: 0