Journal of Experimental Medicine最新文献_第6页

Leukemogenic Kras mutation reprograms multipotent progenitors to facilitate its spread through the hematopoietic system. 白血病Kras突变重编程多能祖细胞以促进其在造血系统中的传播。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-06-02 Epub Date: 2025-03-12 DOI: 10.1084/jem.20240587

Geunhyo Jang, Rosa Park, Eduardo Esteva, Pei-Feng Hsu, Jue Feng, Samik Upadhaya, Catherine M Sawai, Iannis Aifantis, David R Fooksman, Boris Reizis

{"title":"Leukemogenic Kras mutation reprograms multipotent progenitors to facilitate its spread through the hematopoietic system.","authors":"Geunhyo Jang, Rosa Park, Eduardo Esteva, Pei-Feng Hsu, Jue Feng, Samik Upadhaya, Catherine M Sawai, Iannis Aifantis, David R Fooksman, Boris Reizis","doi":"10.1084/jem.20240587","DOIUrl":"10.1084/jem.20240587","url":null,"abstract":"Leukemia-driving mutations are thought to arise in hematopoietic stem cells (HSC), yet the natural history of their spread is poorly understood. We genetically induced mutations within endogenous murine HSC and traced them in unmanipulated animals. In contrast to mutations associated with clonal hematopoiesis (such as Tet2 deletion), the leukemogenic KrasG12D mutation dramatically accelerated HSC contribution to all hematopoietic lineages. The acceleration was mediated by KrasG12D-expressing multipotent progenitors (MPP) that lacked self-renewal but showed increased proliferation and aberrant transcriptome. The deletion of osteopontin, a secreted negative regulator of stem/progenitor cells, delayed the early expansion of mutant progenitors. KrasG12D-carrying cells showed increased CXCR4-driven motility in the bone marrow, and the blockade of CXCR4 reduced the expansion of MPP in vivo. Finally, therapeutic blockade of KRASG12D spared mutant HSC but reduced the expansion of mutant MPP and their mature progeny. Thus, transforming mutations facilitate their own spread from stem cells by reprogramming MPP, creating a preleukemic state via a two-component stem/progenitor circuit.","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/PMC11899982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604941","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

CD301b+ monocyte-derived dendritic cells mediate resistance to radiotherapy. CD301b+单核细胞来源的树突状细胞介导放疗抵抗。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-06-02 Epub Date: 2025-03-27 DOI: 10.1084/jem.20231717

Sirimuvva Tadepalli, Derek R Clements, Hayley M Raquer-McKay, Anja Lüdtke, Sanjana Saravanan, David Seong, Lorraine Vitek, Christopher M Richards, Jan E Carette, Matthias Mack, Andres Gottfried-Blackmore, Edward E Graves, Juliana Idoyaga

引用次数: 0

Identification of a seasonal influenza vaccine-induced broadly protective neuraminidase antibody. 季节性流感疫苗诱导的广泛保护性神经氨酸酶抗体的鉴定。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-06-02 Epub Date: 2025-04-03 DOI: 10.1084/jem.20241930

Anders Madsen, Nisreen M A Okba, Tossapol Pholcharee, Hanover C Matz, Huibin Lv, Maria Ibanez Trullen, Julian Q Zhou, Jackson S Turner, Aaron J Schmitz, Fangjie Han, Stephen C Horvath, Sameer Kumar Malladi, Florian Krammer, Nicholas C Wu, Ali H Ellebedy

{"title":"Identification of a seasonal influenza vaccine-induced broadly protective neuraminidase antibody.","authors":"Anders Madsen, Nisreen M A Okba, Tossapol Pholcharee, Hanover C Matz, Huibin Lv, Maria Ibanez Trullen, Julian Q Zhou, Jackson S Turner, Aaron J Schmitz, Fangjie Han, Stephen C Horvath, Sameer Kumar Malladi, Florian Krammer, Nicholas C Wu, Ali H Ellebedy","doi":"10.1084/jem.20241930","DOIUrl":"10.1084/jem.20241930","url":null,"abstract":"Seasonal influenza viruses cause significant global illness and death annually, and the potential spillover of avian H5N1 poses a serious pandemic threat. Traditional influenza vaccines target the variable hemagglutinin (HA) protein, necessitating annual vaccine updates, while the slower-evolving neuraminidase (NA) presents a promising target for broader protection. We investigated the breadth of anti-NA B cell responses to seasonal influenza vaccination in humans. We screened plasmablast-derived monoclonal antibodies (mAbs) from three donors, identifying 11 clonally distinct NA mAbs from 268 vaccine-specific mAbs. Among these, mAb-297 showed exceptionally broad NA inhibition, effectively protecting mice against lethal doses of influenza A and B viruses, including H5N1. We show that mAb-297 targets a common binding motif in the conserved NA active site. Our findings show that while B cell responses against NA following conventional, egg-derived influenza vaccines are rare, inducing broadly protective NA antibodies through such vaccination remains feasible, highlighting the importance of improving NA immunogens to develop a more broadly protective influenza vaccine.","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/PMC11967445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772527","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

Enteric tuft cell inflammasome activation drives NKp46+ILC3 IL22 via PGD2 and inhibits Salmonella. 肠簇细胞炎症小体活化通过 PGD2 驱动 NKp46+ILC3 IL22 并抑制沙门氏菌。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-06-02 Epub Date: 2025-03-13 DOI: 10.1084/jem.20230803

Madeline J Churchill, Ankit Pandeya, Renate Bauer, Tighe Christopher, Stefanie Krug, Roslyn Honodel, Shuchi Smita, Lindsey Warner, Bridget M Mooney, Alexis R Gibson, Patrick S Mitchell, Elia D Tait Wojno, Isabella Rauch

{"title":"Enteric tuft cell inflammasome activation drives NKp46+ILC3 IL22 via PGD2 and inhibits Salmonella.","authors":"Madeline J Churchill, Ankit Pandeya, Renate Bauer, Tighe Christopher, Stefanie Krug, Roslyn Honodel, Shuchi Smita, Lindsey Warner, Bridget M Mooney, Alexis R Gibson, Patrick S Mitchell, Elia D Tait Wojno, Isabella Rauch","doi":"10.1084/jem.20230803","DOIUrl":"10.1084/jem.20230803","url":null,"abstract":"To distinguish pathogens from commensals, the intestinal epithelium employs cytosolic innate immune sensors. Activation of the NAIP-NLRC4 inflammasome initiates extrusion of infected intestinal epithelial cells (IEC) upon cytosolic bacterial sensing. We previously reported that activation of the inflammasome in tuft cells, which are primarily known for their role in parasitic infections, leads to the release of prostaglandin D2 (PGD2). We observe that NAIP-NLRC4 inflammasome activation in tuft cells leads to an antibacterial response with increased IL-22 and antimicrobial protein levels within the small intestine, which is dependent on PGD2 signaling. A NKp46+ subset of ILC3 expresses the PGD2 receptor CRTH2 and is the source of the increased IL-22. Inflammasome activation in tuft cells also leads to better control of Salmonella Typhimurium in the distal small intestine. However, tuft cells in the cecum and colon are dispensable for antibacterial immunity. These data support that intestinal tuft cells can also induce antibacterial responses, possibly in a tissue-specific manner.","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/PMC11905811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624787","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

MYO1F in neutrophils is required for the response to immune checkpoint blockade therapy. 中性粒细胞MYO1F是免疫检查点阻断治疗应答所必需的。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-06-02 Epub Date: 2025-04-09 DOI: 10.1084/jem.20241957

Yingying Qu, Wenhua Liang, Mingzhu Yu, Chenhui Wang, Min Luo, Lin Zhong, Zhigang Li, Feng Wang

{"title":"MYO1F in neutrophils is required for the response to immune checkpoint blockade therapy.","authors":"Yingying Qu, Wenhua Liang, Mingzhu Yu, Chenhui Wang, Min Luo, Lin Zhong, Zhigang Li, Feng Wang","doi":"10.1084/jem.20241957","DOIUrl":"10.1084/jem.20241957","url":null,"abstract":"Tumor-associated neutrophils (TANs) represent a significant barrier to the effectiveness of immune checkpoint blockade (ICB) therapy. A comprehensive understanding of TANs' regulatory mechanisms is therefore essential for predicting ICB efficacy and improving immunotherapy strategies. Our study reveals that MYO1F is selectively downregulated in neutrophils within both human cancers and murine tumor models, showing a negative correlation with ICB response. Mechanistically, MYO1F normally inhibits neutrophil immunosuppression and proliferation by restraining STAT3 activity. However, during tumorigenesis, tumor-derived TGF-β1 disrupts the binding of SPI1 to intron 8 of Myo1f via DNA methylation, thereby suppressing Myo1f transcription. The resultant decrease in MYO1F reprograms neutrophils into an immunosuppressive state through the STAT3-dependent signaling pathways. This immunosuppressive state further contributes to tumor microenvironment (TME) remodeling by inducing CTL exhaustion. These findings establish MYO1F as a critical regulator within TANs, highlighting its significant role in modulating ICB therapy efficacy.","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/PMC11980683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810747","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 axillary lymphoid organ is an external, experimentally accessible immune organ in the zebrafish. 腋窝淋巴器官是斑马鱼的一种外部免疫器官。

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.20241435

Daniel Castranova, Madeleine I Kenton, Aurora Kraus, Christopher W Dell, Jong S Park, Marina Venero Galanternik, Gilseung Park, Daniel N Lumbantobing, Louis Dye, Miranda Marvel, James Iben, Kiyohito Taimatsu, Van Pham, Reegan J Willms, Lucas Blevens, Tanner F Robertson, Yiran Hou, Anna Huttenlocher, Edan Foley, Lynne R Parenti, J Kimble Frazer, Kedar Narayan, Brant M Weinstein

{"title":"The axillary lymphoid organ is an external, experimentally accessible immune organ in the zebrafish.","authors":"Daniel Castranova, Madeleine I Kenton, Aurora Kraus, Christopher W Dell, Jong S Park, Marina Venero Galanternik, Gilseung Park, Daniel N Lumbantobing, Louis Dye, Miranda Marvel, James Iben, Kiyohito Taimatsu, Van Pham, Reegan J Willms, Lucas Blevens, Tanner F Robertson, Yiran Hou, Anna Huttenlocher, Edan Foley, Lynne R Parenti, J Kimble Frazer, Kedar Narayan, Brant M Weinstein","doi":"10.1084/jem.20241435","DOIUrl":"10.1084/jem.20241435","url":null,"abstract":"Lymph nodes and other secondary lymphoid organs play critical roles in immune surveillance and immune activation in mammals, but the deep internal locations of these organs make it challenging to image and study them in living animals. Here, we describe a previously uncharacterized external immune organ in the zebrafish ideally suited for studying immune cell dynamics in vivo, the axillary lymphoid organ (ALO). This small, translucent organ has an outer cortex teeming with immune cells, an inner medulla with a mesh-like network of fibroblastic reticular cells along which immune cells migrate, and a network of lymphatic vessels draining to a large adjacent lymph sac. Noninvasive high-resolution imaging of transgenically marked immune cells can be carried out in ALOs of living animals, which are readily accessible to external treatment. This newly discovered tissue provides a superb model for dynamic live imaging of immune cells and their interaction with pathogens and surrounding tissues, including blood and lymphatic vessels.","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/PMC11960710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752887","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

PARP7 inhibits type I interferon signaling to prevent autoimmunity and lung disease. PARP7 可抑制 I 型干扰素信号传导，从而预防自身免疫和肺部疾病。

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.20241184

Devon Jeltema, Kennady Knox, Nicole Dobbs, Zhen Tang, Cong Xing, Antonina Araskiewicz, Kun Yang, Ivan Rodriguez Siordia, Jason Matthews, Michael Cohen, Nan Yan

{"title":"PARP7 inhibits type I interferon signaling to prevent autoimmunity and lung disease.","authors":"Devon Jeltema, Kennady Knox, Nicole Dobbs, Zhen Tang, Cong Xing, Antonina Araskiewicz, Kun Yang, Ivan Rodriguez Siordia, Jason Matthews, Michael Cohen, Nan Yan","doi":"10.1084/jem.20241184","DOIUrl":"10.1084/jem.20241184","url":null,"abstract":"Type I IFN (IFN-I) induce hundreds of antiviral genes as well as negative regulators that limit IFN-I signaling. Here, we investigate the family of 16 PARPs and find that 11 PARPs are ISGs, of which 8 PARPs inhibit IFN-I production. PARP7 is the most potent negative feedback regulator of IFN-I production. Using Parp7-/- and Parp7H532A/H532A mice, we show that PARP7 loss leads to systemic autoimmunity characterized by splenomegaly and increased autoantibodies and inflammatory cytokines. PARP7 loss also results in perivascular immune infiltration in the lung that forms tertiary lymphoid structures. Mechanistically, PARP7 inhibits multiple innate immune pathways in a cell-intrinsic and MARylation-dependent manner. PARP7 interacts with IRF3 through the catalytic domain and disrupts the IRF3:CBP/p300 transcriptional holocomplex required for IFN-I production. Irf3-/- or Irf3S1/S1 (transcription defective) or Sting-/- rescues Parp7H532A/H532A mouse autoimmunity and lung disease. Together, our study reveals physiological functions of PARP7 as a negative feedback regulator of IFN-I production that maintains immune homeostasis particularly in the lung.","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/PMC11837972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449298","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

RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs. RBM10缺失通过细胞骨架和细胞外基质mrna的异常剪接促进转移。

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.20241029

Gnana P Krishnamoorthy, Anthony R Glover, Brian R Untch, Nickole Sigcha-Coello, Bin Xu, Dina Vukel, Yi Liu, Vera Tiedje, Jose Mario Bello Pineda, Katherine Berman, Prasanna P Tamarapu, Adrian Acuña-Ruiz, Mahesh Saqcena, Elisa de Stanchina, Laura Boucai, Ronald A Ghossein, Jeffrey A Knauf, Omar Abdel-Wahab, Robert K Bradley, James A Fagin

{"title":"RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs.","authors":"Gnana P Krishnamoorthy, Anthony R Glover, Brian R Untch, Nickole Sigcha-Coello, Bin Xu, Dina Vukel, Yi Liu, Vera Tiedje, Jose Mario Bello Pineda, Katherine Berman, Prasanna P Tamarapu, Adrian Acuña-Ruiz, Mahesh Saqcena, Elisa de Stanchina, Laura Boucai, Ronald A Ghossein, Jeffrey A Knauf, Omar Abdel-Wahab, Robert K Bradley, James A Fagin","doi":"10.1084/jem.20241029","DOIUrl":"10.1084/jem.20241029","url":null,"abstract":"RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon inclusion events included vinculin (VCL), tenascin C (TNC), and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse HrasG12V/Rbm1OKO thyrocytes develop metastases that are reversed by RBM10 expression or by combined knockdown of VCL, CD44, and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusion in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFκB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.","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/PMC11849553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483241","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

Correction: Lymphatic transport in anti-tumor immunity and metastasis. 更正：淋巴运输在抗肿瘤免疫和转移中的作用。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-05-05 Epub Date: 2025-04-04 DOI: 10.1084/jem.2023195403262025c

Mengzhu Sun, Julien Angelillo, Stéphanie Hugues

引用次数: 0

Identifying genetic errors of immunity due to mosaicism. 鉴定由于嵌合引起的免疫基因错误。

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.20241045

Elizabeth G Schmitz, Malachi Griffith, Obi L Griffith, Megan A Cooper

引用次数: 0