Journal of Experimental Medicine最新文献_第4页

Sarah Teichmann: Science always wins if we work together. Sarah Teichmann：如果我们共同努力，科学总会取得胜利。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-09-03 DOI: 10.1084/jem.20251649

Lucie Van Emmenis

引用次数: 0

PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion. PD-1以细胞内在和细胞外在两种方式调节肿瘤浸润性CD8+ T细胞。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-07-24 DOI: 10.1084/jem.20230542

Kristen E Pauken, Samuel C Markson, Thomas S Conway, Vikram R Juneja, Osmaan Shahid, Kelly P Burke, Jared H Rowe, Thao H Nguyen, Jenna L Collier, Jaclyn M L Walsh, Megan E Fung, Jacob M Luber, Alison E Ringel, Jason M Schenkel, Gordon J Freeman, Marcia C Haigis, Meromit Singer, Arlene H Sharpe

{"title":"PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion.","authors":"Kristen E Pauken, Samuel C Markson, Thomas S Conway, Vikram R Juneja, Osmaan Shahid, Kelly P Burke, Jared H Rowe, Thao H Nguyen, Jenna L Collier, Jaclyn M L Walsh, Megan E Fung, Jacob M Luber, Alison E Ringel, Jason M Schenkel, Gordon J Freeman, Marcia C Haigis, Meromit Singer, Arlene H Sharpe","doi":"10.1084/jem.20230542","DOIUrl":"10.1084/jem.20230542","url":null,"abstract":"Although PD-1 inhibitors are FDA-approved for over 25 different cancers, the mechanisms contributing to response remain incompletely understood. To investigate how PD-1-deleted CD8+ T cells influence PD-1-expressing CD8+ T cells in the same tumor microenvironment, we developed an inducible PD-1 knockout (KO) model in which PD-1 is deleted on ∼50% of cells. PD-1 deletion beginning at day 7 after implantation of MC38 tumor cells led to robust tumor control. Remarkably, PD-1-expressing CD8+ T cells in the tumor had increased functionality similar to PD-1 KO CD8+ T cells. Using single-cell RNA-seq and TCR-seq, we found that the major transcriptional changes following PD-1 deletion were shared by PD-1 KO and PD-1-expressing CD8+ T cells, although PD-1 KO clones preferentially expanded. These data suggest PD-1 inhibitors not only exert cell-intrinsic effects but also may promote increased T cell function through non-cell-autonomous mechanisms, which has important implications for design of PD-1-based cancer immunotherapies.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12294807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698712","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

In vivo antibody diversification targeting a conserved coronavirus epitope. 针对保守冠状病毒表位的体内抗体多样化。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-07-17 DOI: 10.1084/jem.20241563

Usha Nair, Ziqi Feng, Madhav Akauliya, Abigail G Esposito, Charles R Crain, Edward D Lamperti, Thavaleak Prum, John E Warner, Lisa Madungwe, Gordon A Dale, Julie Boucau, Gaurav D Gaiha, Meng Yuan, Ian A Wilson, Facundo D Batista

{"title":"In vivo antibody diversification targeting a conserved coronavirus epitope.","authors":"Usha Nair, Ziqi Feng, Madhav Akauliya, Abigail G Esposito, Charles R Crain, Edward D Lamperti, Thavaleak Prum, John E Warner, Lisa Madungwe, Gordon A Dale, Julie Boucau, Gaurav D Gaiha, Meng Yuan, Ian A Wilson, Facundo D Batista","doi":"10.1084/jem.20241563","DOIUrl":"10.1084/jem.20241563","url":null,"abstract":"To explore the use of human B cell receptor (BCR) knock-in mice for broadening antibody responses, we diversified CR3022, a monoclonal antibody (mAb) originally identified in a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) convalescent patient. This mAb targets a conserved epitope on the coronavirus receptor-binding domain (RBD). We took advantage of high- and low-affinity CR3022 BCR knock-in mice and immunized them with SARS-CoV-2 Wuhan RBD trimers to expand the breadth of these antibodies toward this virus. The resulting antibodies retained the ability to neutralize SARS-CoV and exhibited enhanced affinity and neutralization against the SARS-CoV-2 WA1/2020 strain, as well as the Delta (B.1.617.2) and Omicron KP.3 variants. They also showed broadened reactivity to two bat coronaviruses: WIV1 and, to a lesser potency, BtKY72. Structural analysis revealed key mutations that enhanced binding and neutralization, highlighting the importance of epitope accessibility and variant-specific conformations in antibody diversification. These findings demonstrate that human BCR-expressing mouse models can generate effective antibodies with broad neutralizing activity against viral epitopes.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659311","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

Perturbation of calreticulin potentiates CD8+ T cell-mediated antitumor immunity. 钙网蛋白的扰动增强了CD8+ T细胞介导的抗肿瘤免疫。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-08-20 DOI: 10.1084/jem.20242360

Kaiyang Tang, Lijian Wu, Yuanzhi Hu, Teng Xue, Yiteng Jin, Xindi Zhou, Ce Luo, Yaoning Zhao, Linjie Tong, Jie Dai, Di Feng, Zexian Zeng, Deng Pan

{"title":"Perturbation of calreticulin potentiates CD8+ T cell-mediated antitumor immunity.","authors":"Kaiyang Tang, Lijian Wu, Yuanzhi Hu, Teng Xue, Yiteng Jin, Xindi Zhou, Ce Luo, Yaoning Zhao, Linjie Tong, Jie Dai, Di Feng, Zexian Zeng, Deng Pan","doi":"10.1084/jem.20242360","DOIUrl":"https://doi.org/10.1084/jem.20242360","url":null,"abstract":"Effective immunotherapy relies on the presentation of tumor-derived neoantigens on the major histocompatibility complex class I (MHC-I) to activate CD8+ T cells. Deficiencies in this process are a key mechanism of immune evasion and resistance to checkpoint blockade. In this study, using an in vivo CRISPR-Cas9 screen, we unexpectedly found that inactivation of calreticulin (CALR), and other selected components of the peptide-loading complex (PLC), induced robust CD8+ T cell-mediated immune responses. We show that this effect is dependent on the expression of classical MHC-I on tumor cells. Mechanistically, loss of CALR reshaped the MHC-I peptide repertoire, favoring the presentation of low-affinity peptides in murine and human cell lines. Genetic or pharmacological inhibition of PDIA3, another PLC component, similarly induced antitumor effects. These findings reveal a previously unrecognized role of CALR and the PLC in regulating antitumor immunity and suggest that targeting this pathway could be a promising strategy to overcome immune resistance and improve the efficacy of cancer immunotherapies.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural and genetic basis of HIV-1 envelope V2 apex recognition by rhesus broadly neutralizing antibodies. 恒河猴广泛中和抗体识别HIV-1包膜V2顶点的结构和遗传基础。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-08-18 DOI: 10.1084/jem.20250638

Ryan S Roark, Rumi Habib, Jason Gorman, Hui Li, Andrew Jesse Connell, Mattia Bonsignori, Yicheng Guo, Michael P Hogarty, Adam S Olia, Kirsten J Sowers, Baoshan Zhang, Frederic Bibollet-Ruche, Tatsiana Bylund, Sean Callaghan, John W Carey, Gabriele Cerutti, Darcy R Harris, Wanting He, Emily Lewis, Tracy Liu, Rosemarie D Mason, Yujie Qiao, Younghoon Park, Juliette M Rando, Ajay Singh, Jeremy J Wolff, Q Paula Lei, Mark K Louder, Raiees Andrabi, Nicole A Doria-Rose, Kevin O Saunders, Michael S Seaman, Barton F Haynes, Daniel W Kulp, John R Mascola, Mario Roederer, Theodore C Pierson, Zizhang Sheng, Beatrice H Hahn, George M Shaw, Peter D Kwong, Lawrence Shapiro

{"title":"Structural and genetic basis of HIV-1 envelope V2 apex recognition by rhesus broadly neutralizing antibodies.","authors":"Ryan S Roark, Rumi Habib, Jason Gorman, Hui Li, Andrew Jesse Connell, Mattia Bonsignori, Yicheng Guo, Michael P Hogarty, Adam S Olia, Kirsten J Sowers, Baoshan Zhang, Frederic Bibollet-Ruche, Tatsiana Bylund, Sean Callaghan, John W Carey, Gabriele Cerutti, Darcy R Harris, Wanting He, Emily Lewis, Tracy Liu, Rosemarie D Mason, Yujie Qiao, Younghoon Park, Juliette M Rando, Ajay Singh, Jeremy J Wolff, Q Paula Lei, Mark K Louder, Raiees Andrabi, Nicole A Doria-Rose, Kevin O Saunders, Michael S Seaman, Barton F Haynes, Daniel W Kulp, John R Mascola, Mario Roederer, Theodore C Pierson, Zizhang Sheng, Beatrice H Hahn, George M Shaw, Peter D Kwong, Lawrence Shapiro","doi":"10.1084/jem.20250638","DOIUrl":"10.1084/jem.20250638","url":null,"abstract":"Broadly neutralizing antibodies targeting the V2 apex of HIV-1 envelope are desired as vaccine design templates, but few have been described. Here, we report 11 lineages of V2 apex-neutralizing antibodies from simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and determine cryo-EM structures for 9. A single V2 apex-neutralizing lineage accounted for cross-clade breadth in most macaques, and somatic hypermutation relative to breadth was generally low, exemplified by antibody V033-a.01 with <5% nucleotide mutation and 37% breadth (208-strain panel). Envelope complex structures revealed eight different antibody classes (one multi-donor) and the complete repertoire of all five possible recognition topologies, recapitulating canonical human modes of apex insertion and C-strand hydrogen bonding. Despite this diversity in recognition, all rhesus-V2 apex antibodies were derived from reading frame two of the DH3-15*01 gene. Collectively, these results define-in rhesus-the structural and genetic basis of HIV-1 V2 apex recognition and demonstrate unprecedented structural plasticity of a highly selected immunogenetic element.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873479","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

Repertoire, function, and structure of serological antibodies induced by the R21/Matrix-M malaria vaccine. R21/Matrix-M疟疾疫苗诱导的血清学抗体的库、功能和结构

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-07-28 DOI: 10.1084/jem.20241908

Jonathan R McDaniel, William N Voss, Georgina Bowyer, Scott A Rush, Alexandra J Spencer, Duncan Bellamy, Marta Ulaszewska, Jule Goike, Scott Gregory, C Richter King, Jason S McLellan, Adrian V S Hill, George Georgiou, Katie J Ewer, Gregory C Ippolito

{"title":"Repertoire, function, and structure of serological antibodies induced by the R21/Matrix-M malaria vaccine.","authors":"Jonathan R McDaniel, William N Voss, Georgina Bowyer, Scott A Rush, Alexandra J Spencer, Duncan Bellamy, Marta Ulaszewska, Jule Goike, Scott Gregory, C Richter King, Jason S McLellan, Adrian V S Hill, George Georgiou, Katie J Ewer, Gregory C Ippolito","doi":"10.1084/jem.20241908","DOIUrl":"10.1084/jem.20241908","url":null,"abstract":"The World Health Organization (WHO) recently recommended the programmatic use of the R21/Matrix-M vaccine for Plasmodium falciparum malaria prevention in children living in malaria-endemic areas. To determine its effects on humoral immunity, we conducted a proteomic analysis of polyclonal IgG antibodies directed against the NANP tetrapeptide of the circumsporozoite protein (CSP), which comprises the vaccine's core immunogen. In 10 malaria-naïve adult volunteers, R21/Matrix-M induced polarized IgG anti-NANP repertoires, heavily skewed for IGHV3-30/3-33 genes bearing minimal somatic mutation, which remained static in composition following a controlled human malaria infection challenge. Notably, these vaccine-generated antibodies cross-reacted with another protective CSP epitope, the N-terminal junction region, despite its absence from the R21 construct. NANP-specific IGHV3-30/3-33 mAbs mined from polyclonal IgG repertoires blocked sporozoite invasion in vitro and prevented parasitemia in vivo. Overall, R21/Matrix-M elicits polarized, minimally mutated, polyclonal IgG responses that can target multiple protective CSP epitopes, offering molecular insight into the serological basis for its demonstrated efficacy against P. falciparum malaria.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144731592","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 STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency. STING通路驱动NGLY1缺乏症的非炎症性神经变性。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-07-11 DOI: 10.1084/jem.20242296

Kun Yang, Gustavo Torres-Ramirez, Nicole Dobbs, Jie Han, Makoto Asahina, Reiko Fujinawa, Kun Song, Yun Liu, Weichun Lin, Angelica Oviedo, Chuo Chen, Lei Zhu, William F Mueller, Kevin Lee, Tadashi Suzuki, Nan Yan

{"title":"The STING pathway drives noninflammatory neurodegeneration in NGLY1 deficiency.","authors":"Kun Yang, Gustavo Torres-Ramirez, Nicole Dobbs, Jie Han, Makoto Asahina, Reiko Fujinawa, Kun Song, Yun Liu, Weichun Lin, Angelica Oviedo, Chuo Chen, Lei Zhu, William F Mueller, Kevin Lee, Tadashi Suzuki, Nan Yan","doi":"10.1084/jem.20242296","DOIUrl":"10.1084/jem.20242296","url":null,"abstract":"The STING pathway is increasingly recognized as a key regulator of neuroinflammation in neurodegenerative disease, but its role in noninflammatory conditions remains unclear. We generated a postnatal inducible whole-body Ngly1 knockout mouse (iNgly1-/-) to model NGLY1 deficiency, an early-onset neurodegenerative disorder. iNgly1-/- mice exhibit progressive motor deficits, Purkinje cell loss, and shortened lifespan without evidence of gliosis or immune activation. Cell type-specific deletion of Ngly1 in Purkinje cells or microglia failed to induce disease, suggesting multiple cell-intrinsic and cell-extrinsic signals are required. Genetic ablation of Sting1 in iNgly1-/- mice rescues Purkinje cell loss, improves motor function, and extends lifespan. Single-nucleus RNA sequencing reveals proteostasis disruption in Purkinje cells, altered cerebellar granule cell subpopulations, and STING-dependent suppression of cholesterol biosynthesis in glia. Pharmacological inhibition of STING with an orally bioactive antagonist, VS-X4, significantly mitigates neuropathology and motor disease. These findings identify STING as a key mediator of neuropathology in NGLY1 deficiency and implicate a role of STING in noninflammatory neurological disease.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12249164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612174","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: Suppression of local type I interferon by gut microbiota-derived butyrate impairs antitumor effects of ionizing radiation. 更正：肠道微生物来源的丁酸盐抑制局部I型干扰素会损害电离辐射的抗肿瘤作用。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-09-19 DOI: 10.1084/jem.2020191509032025c

Kaiting Yang, Yuzhu Hou, Yuan Zhang, Hua Liang, Anukriti Sharma, Wenxin Zheng, Liangliang Wang, Rolando Torres, Ken Tatebe, Steven J Chmura, Sean P Pitroda, Jack A Gilbert, Yang-Xin Fu, Ralph R Weichselbaum

引用次数: 0

Target acquired: Lock-on bacterial immunopeptides. 目标获得：锁定细菌免疫肽。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-07-29 DOI: 10.1084/jem.20251232

Patrick Willems, Lyudmila Kovalchuke, Francis Impens

引用次数: 0

Early and opposing neutrophil and CD4 T cell responses shape pulmonary tuberculosis pathology. 早期和对立的中性粒细胞和CD4 T细胞反应形成肺结核病理。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-07-30 DOI: 10.1084/jem.20250161

Benjamin H Gern, Josepha M Klas, Kimberly A Foster, Molly E Kanagy, Sara B Cohen, Courtney R Plumlee, Fergal J Duffy, Maxwell L Neal, Mehnaz Halima, Andrew T Gustin, Sylvia M Stull, Jasmine J Wilson, Alan H Diercks, Alan Aderem, Michael Gale, John D Aitchison, Michael Y Gerner, Kevin B Urdahl

{"title":"Early and opposing neutrophil and CD4 T cell responses shape pulmonary tuberculosis pathology.","authors":"Benjamin H Gern, Josepha M Klas, Kimberly A Foster, Molly E Kanagy, Sara B Cohen, Courtney R Plumlee, Fergal J Duffy, Maxwell L Neal, Mehnaz Halima, Andrew T Gustin, Sylvia M Stull, Jasmine J Wilson, Alan H Diercks, Alan Aderem, Michael Gale, John D Aitchison, Michael Y Gerner, Kevin B Urdahl","doi":"10.1084/jem.20250161","DOIUrl":"10.1084/jem.20250161","url":null,"abstract":"Pulmonary Mycobacterium tuberculosis (Mtb) infection results in a variety of heterogeneous lesion structures, from necrotic granulomas to alveolitis, but the mechanisms regulating their development remain unclear. Using a mouse model of concomitant immunity and subsequent aerosol infection, we demonstrate that counter regulation between neutrophils and CD4 T cells occurs very early during infection and governs these distinct pathologies. In primary Mtb infection, a dysregulated feed-forward circuit of neutrophil recruitment occurs, in which neutrophils hinder CD4 T cell interactions with infected macrophages, cause granuloma necrosis, and establish a replicative niche that drives a two-log increase in lung bacterial burden. Conversely, the rapid recruitment and activation of T cells due to concomitant immunity promotes local macrophage activation and dampens detrimental neutrophil responses. Together, these studies uncover fundamental determinants of tuberculosis lung pathology, which have important implications for new strategies to prevent or treat tuberculosis.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742247","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