Journal of Experimental Medicine最新文献_第7页

KLF family members control expression of genes required for tissue macrophage identities. KLF家族成员控制组织巨噬细胞身份所需基因的表达。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-05-05 Epub Date: 2025-03-12 DOI: 10.1084/jem.20240379

Kathleen Pestal, Leianna C Slayden, Gregory M Barton

引用次数: 0

Early Notch signals from fibroblastic reticular cells program effector CD8+ T cell differentiation. 来自成纤维网状细胞的早期Notch信号程序效应CD8+ T细胞分化。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-05-05 Epub Date: 2025-03-20 DOI: 10.1084/jem.20231758

Dave Maurice De Sousa, Eric Perkey, Laure Le Corre, Salix Boulet, Daniela Gómez Atria, Anneka Allman, Frédéric Duval, Jean-François Daudelin, Joshua D Brandstadter, Katlyn Lederer, Sarah Mezrag, Livia Odagiu, Myriam Ennajimi, Marion Sarrias, Hélène Decaluwe, Ute Koch, Freddy Radtke, Burkhard Ludewig, Christian W Siebel, Ivan Maillard, Nathalie Labrecque

{"title":"Early Notch signals from fibroblastic reticular cells program effector CD8+ T cell differentiation.","authors":"Dave Maurice De Sousa, Eric Perkey, Laure Le Corre, Salix Boulet, Daniela Gómez Atria, Anneka Allman, Frédéric Duval, Jean-François Daudelin, Joshua D Brandstadter, Katlyn Lederer, Sarah Mezrag, Livia Odagiu, Myriam Ennajimi, Marion Sarrias, Hélène Decaluwe, Ute Koch, Freddy Radtke, Burkhard Ludewig, Christian W Siebel, Ivan Maillard, Nathalie Labrecque","doi":"10.1084/jem.20231758","DOIUrl":"10.1084/jem.20231758","url":null,"abstract":"A better understanding of the mechanisms regulating CD8+ T cell differentiation is essential to develop new strategies to fight infections and cancer. Using genetic mouse models and blocking antibodies, we uncovered cellular and molecular mechanisms by which Notch signaling favors the efficient generation of effector CD8+ T cells. Fibroblastic reticular cells from secondary lymphoid organs, but not dendritic cells, were the dominant source of Notch signals in T cells via Delta-like1/4 ligands within the first 3 days of immune responses to vaccination or infection. Using transcriptional and epigenetic studies, we identified a unique Notch-driven T cell-specific signature. Early Notch signals were associated with chromatin opening in regions occupied by bZIP transcription factors, specifically BATF, known to be important for CD8+ T cell differentiation. Overall, we show that fibroblastic reticular cell niches control the ultimate molecular and functional fate of CD8+ T cells after vaccination or infection through the delivery of early Notch signals.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663650","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

Primary disorders of polyubiquitination: Dual roles in autoinflammation and immunodeficiency. 多泛素化的原发性疾病：在自身炎症和免疫缺陷中的双重作用。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-05-05 Epub Date: 2025-04-15 DOI: 10.1084/jem.20241047

András N Spaan, Bertrand Boisson, Seth L Masters

引用次数: 0

Splicing factor RBM10 loss fuels thyroid cancer metastasis. 剪接因子RBM10缺失促进甲状腺癌转移

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-05-05 Epub Date: 2025-02-24 DOI: 10.1084/jem.20250050

Kevin Coughlin, Ledong Wan

引用次数: 0

Intravital imaging of pulmonary lymphatics in inflammation and metastatic cancer. 肺淋巴管在炎症和转移性癌中的活体显像。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-05-05 Epub Date: 2025-02-19 DOI: 10.1084/jem.20241359

Simon J Cleary, Longhui Qiu, Yurim Seo, Peter Baluk, Dan Liu, Nina K Serwas, Catherine A Taylor, Dongliang Zhang, Jason G Cyster, Donald M McDonald, Matthew F Krummel, Mark R Looney

{"title":"Intravital imaging of pulmonary lymphatics in inflammation and metastatic cancer.","authors":"Simon J Cleary, Longhui Qiu, Yurim Seo, Peter Baluk, Dan Liu, Nina K Serwas, Catherine A Taylor, Dongliang Zhang, Jason G Cyster, Donald M McDonald, Matthew F Krummel, Mark R Looney","doi":"10.1084/jem.20241359","DOIUrl":"10.1084/jem.20241359","url":null,"abstract":"Intravital microscopy has enabled the study of immune dynamics in the pulmonary microvasculature, but many key events remain unseen because they occur in deeper lung regions. We therefore developed a technique for stabilized intravital imaging of bronchovascular cuffs and collecting lymphatics surrounding pulmonary veins in mice. Intravital imaging of pulmonary lymphatics revealed ventilation dependence of steady-state lung lymph flow and ventilation-independent lymph flow during inflammation. We imaged the rapid exodus of migratory dendritic cells through lung lymphatics following inflammation and measured effects of pharmacologic and genetic interventions targeting chemokine signaling. Intravital imaging also captured lymphatic immune surveillance of lung-metastatic cancers and lymphatic metastasis of cancer cells. To our knowledge, this is the first imaging of lymph flow and leukocyte migration through intact pulmonary lymphatics. This approach will enable studies of protective and maladaptive processes unfolding within the lungs and in other previously inaccessible locations.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449246","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

Vaccinology: Getting our modernization act together. 疫苗学：让我们的现代化行动起来。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-05-05 Epub Date: 2025-04-22 DOI: 10.1084/jem.20240961

Ofer Levy

引用次数: 0

Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control. 小胶质细胞中ATG7的缺失会损害UPR，引发铁下垂，并削弱淀粉样蛋白病理控制。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-04-07 Epub Date: 2025-02-13 DOI: 10.1084/jem.20230173

Zhangying Cai, Shoutang Wang, Siyan Cao, Yun Chen, Silvia Penati, Vincent Peng, Carla M Yuede, Wandy L Beatty, Kent Lin, Yiyang Zhu, Yingyue Zhou, Marco Colonna

{"title":"Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control.","authors":"Zhangying Cai, Shoutang Wang, Siyan Cao, Yun Chen, Silvia Penati, Vincent Peng, Carla M Yuede, Wandy L Beatty, Kent Lin, Yiyang Zhu, Yingyue Zhou, Marco Colonna","doi":"10.1084/jem.20230173","DOIUrl":"10.1084/jem.20230173","url":null,"abstract":"Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer's disease (AD) is to contain proteotoxic amyloid-β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here, we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical, and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ buildup, UPR reduction and increased oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation and oxidative stress as they age.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407703","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

The MLL3/GRHL2 complex regulates malignant transformation and anti-tumor immunity in squamous cancer. MLL3/GRHL2复合物调控鳞状肿瘤的恶性转化和抗肿瘤免疫。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-04-07 Epub Date: 2025-02-18 DOI: 10.1084/jem.20240758

Chehyun Nam, Guowei Huang, Yueyuan Zheng, Hua Zhao, Yuhao Pan, Boyan Hu, Talia Wenger, Hieu T Van, Li-Yan Xu, En-Min Li, H Phillip Koeffler, Kai Ge, Yali Dou, Uttam K Sinha, Young Min Park, De-Chen Lin

{"title":"The MLL3/GRHL2 complex regulates malignant transformation and anti-tumor immunity in squamous cancer.","authors":"Chehyun Nam, Guowei Huang, Yueyuan Zheng, Hua Zhao, Yuhao Pan, Boyan Hu, Talia Wenger, Hieu T Van, Li-Yan Xu, En-Min Li, H Phillip Koeffler, Kai Ge, Yali Dou, Uttam K Sinha, Young Min Park, De-Chen Lin","doi":"10.1084/jem.20240758","DOIUrl":"10.1084/jem.20240758","url":null,"abstract":"Upper aerodigestive squamous cell carcinoma (UASCC) presents significant challenges in clinical management due to its aggressive nature. Here, we elucidate the role of MLL3 mutations as early, clonal genomic events in UASCC tumorigenesis, highlighting their role as foundational drivers of cancer development. Utilizing CRISPR-edited, cross-species organoid modeling, we demonstrate that loss of MLL3 contributes to early squamous neoplastic evolution. Furthermore, we identify an MLL3/GRHL2 protein complex that regulates the UASCC epigenome, particularly impacting immune response pathways. Notably, a novel MLL3/GRHL2-IRF1 axis promotes the expression of Th1 chemokines, enhancing anti-tumor immunity by facilitating T cell infiltration into the tumor microenvironment. Consequently, MLL3 regulates the in vivo efficacy of immune checkpoint blockade (ICB) therapy, corroborated by the strong association between MLL3 expression and human patients' clinical response to ICB therapy. Our work underscores the significance of MLL3 in UASCC pathogenesis and highlights the interplay between MLL3/GRHL2 and immune response pathways as potential therapeutic targets for UASCC treatment.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441087","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

Estrogen influences class-switched memory B cell frequency only in humans with two X chromosomes. 雌激素仅在具有两条X染色体的人类中影响类别转换记忆B细胞频率。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-04-07 Epub Date: 2025-03-06 DOI: 10.1084/jem.20241253

Hannah Peckham, Anna Radziszewska, Justyna Sikora, Nina M de Gruijter, Restuadi Restuadi, Melissa Kartawinata, Lucia Martin-Gutierrez, George A Robinson, Claire T Deakin, Lucy R Wedderburn, Elizabeth C Jury, Gary Butler, Emma S Chambers, Elizabeth C Rosser, Coziana Ciurtin

{"title":"Estrogen influences class-switched memory B cell frequency only in humans with two X chromosomes.","authors":"Hannah Peckham, Anna Radziszewska, Justyna Sikora, Nina M de Gruijter, Restuadi Restuadi, Melissa Kartawinata, Lucia Martin-Gutierrez, George A Robinson, Claire T Deakin, Lucy R Wedderburn, Elizabeth C Jury, Gary Butler, Emma S Chambers, Elizabeth C Rosser, Coziana Ciurtin","doi":"10.1084/jem.20241253","DOIUrl":"10.1084/jem.20241253","url":null,"abstract":"Sex differences in immunity are well-documented, though mechanisms underpinning these differences remain ill-defined. Here, in a human-only ex vivo study, we demonstrate that postpubertal cisgender females have higher levels of CD19+CD27+IgD- class-switched memory B cells compared with age-matched cisgender males. This increase is only observed after puberty and before menopause, suggesting a strong influence for sex hormones. Accordingly, B cells express high levels of estrogen receptor 2 (ESR2), and class-switch-regulating genes are enriched for ESR2-binding sites. In a gender-diverse cohort, blockade of natal estrogen in transgender males (XX karyotype) reduced class-switched memory B cell frequency, while gender-affirming estradiol treatment in transgender females (XY karyotype) did not increase these levels. In postmenopausal cis-females, class-switched memory B cells were increased in those taking hormone replacement therapy (HRT) compared with those who were not. These data demonstrate that sex hormones and chromosomes work in tandem to impact immune responses, with estrogen only influencing the frequency of class-switched memory B cells in individuals with an XX chromosomal background.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572916","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

Periductal fibroblasts participate in liver homeostasis, fibrosis, and tumorigenesis. 导管周围成纤维细胞参与肝脏稳态、纤维化和肿瘤发生。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-04-07 Epub Date: 2025-01-31 DOI: 10.1084/jem.20232123

Shan-Shan Wang, Jia Yuan, Xinyu Thomas Tang, Xiujuan Yin, Ke Fang, Lin Veronica Chen, Zhenggang Ren, Bo O Zhou

{"title":"Periductal fibroblasts participate in liver homeostasis, fibrosis, and tumorigenesis.","authors":"Shan-Shan Wang, Jia Yuan, Xinyu Thomas Tang, Xiujuan Yin, Ke Fang, Lin Veronica Chen, Zhenggang Ren, Bo O Zhou","doi":"10.1084/jem.20232123","DOIUrl":"10.1084/jem.20232123","url":null,"abstract":"Hepatic fibroblasts comprise groups of stromal cells in the liver that are phenotypically distinct from hepatic stellate cells. However, their physiology is poorly understood. By single-cell RNA sequencing, we identified Cd34 and Dpt as hepatic fibroblast-specific genes. Cd34-CreER labeled periportal-venous and periductal fibroblasts, but few pericentral-venous fibroblasts. Cd34+ fibroblasts generated ∼25% of myofibroblasts in periportal fibrosis and ∼40% of cancer-associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma (ICC). Myofibroblast formation by Cd34+ fibroblasts required Tgfbr2. Depletion of Cd34+ fibroblasts increased the frequency of the ductal epithelial cells under homeostasis and accelerated the progression of ICC. Dpt-CreER labeled periportal- and pericentral-venous fibroblasts, but much less periductal fibroblasts. Dpt+ cells generated ∼15% of myofibroblasts in periportal fibrosis, but few myofibroblasts in pericentral fibrosis or CAFs in ICC. Thus, an orthogonal combination of Cd34-CreER and Dpt-CreER dissected the fates of periductal, periportal-venous, and pericentral-venous fibroblasts. Both periductal and periportal-venous fibroblasts contribute to liver fibrosis. Periductal fibroblasts also contribute to ductal homeostasis and ICC progression.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064604","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