{"title":"KLF2 expression in IgG plasma cells at their induction site regulates the migration program.","authors":"Wataru Ise, Takuya Koike, Nozomi Shimada, Hiromi Yamamoto, Yuki Tai, Taiichiro Shirai, Ryoji Kawakami, Mana Kuwabara, Chie Kawai, Kyoko Shida, Takeshi Inoue, Nozomi Hojo, Kenji Ichiyama, Shimon Sakaguchi, Katsuyuki Shiroguchi, Kazuhiro Suzuki, Tomohiro Kurosaki","doi":"10.1084/jem.20241019","DOIUrl":"10.1084/jem.20241019","url":null,"abstract":"<p><p>Newly generated plasma cells in secondary lymphoid organs migrate to niches in the bone marrow, wherein they survive as long-lived plasma cells (LLPCs). Although LLPCs have been extensively characterized, it is still unclear what the key determinant(s) are for plasma cell longevity. One model postulates that plasma cell heterogeneity is established at the induction site, thereby instructing their longevity. Here, we found that, among newly generated IgG plasma cells, integrin β7hi marks plasma cells predisposed to home to the bone marrow, whereas integrin β7lo cells remain in secondary lymphoid organs. Mechanistically, this egress-prone fraction had a higher expression of the KLF2 transcription factor, the loss of which resulted in defective egress by downregulating S1PR1 and CD11b. Disruption of plasma cell egress results in defective antibody durability, thereby making mice more susceptible to influenza reinfection. Thus, the migration program of plasma cells established at the induction site plays a critical role in determining antibody durability.</p>","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/PMC11841683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457733","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}
Shir Bergson, Ofer Sarig, Moshe Giladi, Janan Mohamad, Mariana Mogezel-Salem, Karina Smorodinsky-Atias, Ofir Sade, Bar Manori, Sari Assaf, Kiril Malovitski, Yarden Feller, Mor Pavlovsky, Stefan Hainzl, Thomas Kocher, Julia I Hummel, Noy Eretz Kdosha, Lubna Gazi Khair, Roland Zauner, Josefina Pinon Hofbauer, Ruby Shalom-Feuerstein, Verena Wally, Ulrich Koller, Liat Samuelov, Yoni Haitin, Uri Ashery, Rotem Rubinstein, Eli Sprecher
{"title":"HMCN1 variants aggravate epidermolysis bullosa simplex phenotype.","authors":"Shir Bergson, Ofer Sarig, Moshe Giladi, Janan Mohamad, Mariana Mogezel-Salem, Karina Smorodinsky-Atias, Ofir Sade, Bar Manori, Sari Assaf, Kiril Malovitski, Yarden Feller, Mor Pavlovsky, Stefan Hainzl, Thomas Kocher, Julia I Hummel, Noy Eretz Kdosha, Lubna Gazi Khair, Roland Zauner, Josefina Pinon Hofbauer, Ruby Shalom-Feuerstein, Verena Wally, Ulrich Koller, Liat Samuelov, Yoni Haitin, Uri Ashery, Rotem Rubinstein, Eli Sprecher","doi":"10.1084/jem.20240827","DOIUrl":"10.1084/jem.20240827","url":null,"abstract":"<p><p>Epidermolysis bullosa simplex (EBS) refers to a heterogeneous group of inherited skin disorders characterized by blister formation within the basal cell layer. The disease is characterized by marked variations in phenotype severity, suggesting co-inheritance of genetic modifiers. We identified three deleterious variants in HMCN1 that co-segregated with a more severe phenotype in a group of 20 individuals with EBS caused by mutations in KRT14, encoding keratin 14 (K14). HMCN1 codes for hemicentin-1. Protein modeling, molecular dynamics simulations, and functional experiments showed that all three HMCN1 variants disrupt protein stability. Hemicentin-1 was found to be expressed in human skin above the BMZ. Using yeast-2-hybrid, co-immunoprecipitation, and proximity ligation assays, we found that hemicentin-1 binds K14. Three-dimensional skin equivalents grown from hemicentin-1-deficient cells were found to spontaneously develop subepidermal blisters, and HMCN1 downregulation was found to reduce keratin intermediate filament formation. In conclusion, hemicentin-1 binds K14 and contributes to BMZ stability, which explains the fact that deleterious HMCN1 variants co-segregate with a more severe phenotype in KRT14-associated EBS.</p>","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/PMC11841684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457716","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}
Kathleen Pestal, Leianna C Slayden, Gregory M Barton
{"title":"KLF family members control expression of genes required for tissue macrophage identities.","authors":"Kathleen Pestal, Leianna C Slayden, Gregory M Barton","doi":"10.1084/jem.20240379","DOIUrl":"10.1084/jem.20240379","url":null,"abstract":"<p><p>Tissue-resident macrophages adopt distinct gene expression profiles and exhibit functional specialization based on their tissue of residence. Recent studies have begun to define the signals and transcription factors that induce these identities. Here we describe an unexpected and specific role for the broadly expressed transcription factor Krüppel-like factor 2 (KLF2) in the development of embryonically derived large cavity macrophages (LCMs) in the serous cavities. KLF2 not only directly regulates the transcription of genes previously shown to specify LCM identity, such as retinoic acid receptors and GATA6, but also is required for induction of many other transcripts that define the identity of these cells. Our results suggest that KLF4 may similarly regulate the identity of alveolar macrophages in the lung. These data demonstrate that broadly expressed transcription factors, such as group 2 KLFs, can play important roles in the specification of distinct identities of tissue-resident macrophages.</p>","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/PMC11899981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605022","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
{"title":"Splicing factor RBM10 loss fuels thyroid cancer metastasis.","authors":"Kevin Coughlin, Ledong Wan","doi":"10.1084/jem.20250050","DOIUrl":"10.1084/jem.20250050","url":null,"abstract":"<p><p>In this issue of JEM, Krishnamoorthy et al. (https://doi.org/10.1084/jem.20241029) identify the loss of the splicing factor RBM10 as a driver of metastasis in thyroid cancer through the regulation of RNA splicing. The synthetic lethal interaction between NF-κB and RBM10 loss reveals a potential therapeutic vulnerability.</p>","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/PMC11849749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483242","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
