Journal of Experimental Medicine最新文献_第2页

MCRS1 sensitizes T cell-dependent immunotherapy by augmenting MHC-I expression in solid tumors. MCRS1 通过增强实体瘤中 MHC-I 的表达，使依赖 T 细胞的免疫疗法变得敏感。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-12-02 Epub Date: 2024-11-15 DOI: 10.1084/jem.20240959

Xue Li, Han Yi, Zheyu Jin, Kaitao Jiang, Kangkang Xue, Jin Wang, Yuping Qian, Qian Xiang, Sijing Zhu, Runhe Yan, Yulong Yang, Shenfei Sun, Kai Li, Zichu Zhou, Wei Yu, Ning Jiang, Chen Ding, Xinhua Lin, Jiang Zhong, Yuchao Dong, Yanfang Liu, Xiaofei Yu

{"title":"MCRS1 sensitizes T cell-dependent immunotherapy by augmenting MHC-I expression in solid tumors.","authors":"Xue Li, Han Yi, Zheyu Jin, Kaitao Jiang, Kangkang Xue, Jin Wang, Yuping Qian, Qian Xiang, Sijing Zhu, Runhe Yan, Yulong Yang, Shenfei Sun, Kai Li, Zichu Zhou, Wei Yu, Ning Jiang, Chen Ding, Xinhua Lin, Jiang Zhong, Yuchao Dong, Yanfang Liu, Xiaofei Yu","doi":"10.1084/jem.20240959","DOIUrl":"10.1084/jem.20240959","url":null,"abstract":"Dampened antigen presentation underscores the resistance of pancreatic cancer to T cell-mediated anti-tumor immunity, rendering immunotherapy largely ineffective. By high-throughput CRISPR activation perturbation, we discovered that the transcriptional regulator MCRS1 significantly augmented the sensitivity of mouse pancreatic cancer cells to T cell immunity in vitro and in vivo. Mechanistically, MCRS1 interacted with the transcription factor and genome organizer YY1 to coordinately increase the chromatin accessibility and expression of MHC-I genes. Elevated MCRS1 subverted MHC-I suppression and activated anti-tumor T cells, which sensitized mouse pancreatic cancer to α-PD-1 therapy. Remarkably, high MCRS1 expression was associated with increased T cell infiltration and extended survival of patients with pancreatic cancer and was predictive of favorable responses to α-PD-1 therapy in patients with lung cancer. Together, our study uncovers that MCRS1 sensitizes cancer cells to T cell immunity by transcriptionally subverting MHC-I suppression, which enhances the effectiveness of α-PD-1 therapy in mice and humans, paving the way to further improve immunotherapy against solid tumors.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11572484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639032","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

Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signaling. 嘌呤能信号对 IFN-γ 和 IL-4 协同产生的非常规 T 细胞的选择性调控。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-12-02 Epub Date: 2024-11-19 DOI: 10.1084/jem.20240354

Calvin Xu, Andreas Obers, Minyi Qin, Alice Brandli, Joelyn Wong, Xin Huang, Allison Clatch, Aly Fayed, Graham Starkey, Rohit D'Costa, Claire L Gordon, Jeffrey Y W Mak, David P Fairlie, Lynette Beattie, Laura K Mackay, Dale I Godfrey, Hui-Fern Koay

{"title":"Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signaling.","authors":"Calvin Xu, Andreas Obers, Minyi Qin, Alice Brandli, Joelyn Wong, Xin Huang, Allison Clatch, Aly Fayed, Graham Starkey, Rohit D'Costa, Claire L Gordon, Jeffrey Y W Mak, David P Fairlie, Lynette Beattie, Laura K Mackay, Dale I Godfrey, Hui-Fern Koay","doi":"10.1084/jem.20240354","DOIUrl":"10.1084/jem.20240354","url":null,"abstract":"Unconventional T cells, including mucosal-associated invariant T (MAIT), natural killer T (NKT), and gamma-delta T (γδT) cells, comprise distinct T-bet+, IFN-γ+ and RORγt+, IL-17+ subsets which play differential roles in health and disease. NKT1 cells are susceptible to ARTC2-mediated P2X7 receptor (P2RX7) activation, but the effects on other unconventional T-cell types are unknown. Here, we show that MAIT, γδT, and NKT cells express P2RX7 and are sensitive to P2RX7-mediated cell death. Mouse peripheral T-bet+ MAIT1, γδT1, and NKT1 cells, especially in liver, co-express ARTC2 and P2RX7. These markers could be further upregulated upon exposure to retinoic acid. Blocking ARTC2 or inhibiting P2RX7 protected MAIT1, γδT1, and NKT1 cells from cell death, enhanced their survival in vivo, and increased the number of IFN-γ-secreting cells without affecting IL-17 production. Importantly, this revealed the existence of IFN-γ and IL-4 co-producing unconventional T-cell populations normally lost upon isolation due to ARTC2/P2RX7-induced death. Administering extracellular NAD in vivo activated this pathway, depleting P2RX7-sensitive unconventional T cells. Our study reveals ARTC2/P2RX7 as a common regulatory axis modulating the unconventional T-cell compartment, affecting the viability of IFN-γ- and IL-4-producing T cells, offering important insights to facilitate future studies into how these cells can be regulated in health and disease.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668017","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

Basophils: Regulators of lung inflammation over space and time. 嗜碱性粒细胞：肺部炎症的时空调节器

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-12-02 Epub Date: 2024-10-25 DOI: 10.1084/jem.20241663

Régis Joulia, Clare M Lloyd

引用次数: 0

Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer. hTERT/telomerase/telomere 的抑制介导了奥希替尼对表皮生长因子受体突变肺癌的疗效。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-11-04 Epub Date: 2024-09-19 DOI: 10.1084/jem.20240435

Zhen Chen, Karin A Vallega, Dongsheng Wang, Zihan Quan, Songqing Fan, Qiming Wang, Ticiana Leal, Suresh S Ramalingam, Shi-Yong Sun

{"title":"Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer.","authors":"Zhen Chen, Karin A Vallega, Dongsheng Wang, Zihan Quan, Songqing Fan, Qiming Wang, Ticiana Leal, Suresh S Ramalingam, Shi-Yong Sun","doi":"10.1084/jem.20240435","DOIUrl":"10.1084/jem.20240435","url":null,"abstract":"The inevitable acquired resistance to osimertinib (AZD9291), an FDA-approved third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating or T790M resistant mutations, limits its long-term clinical benefit. Telomere maintenance via telomerase reactivation is linked to uncontrolled cell growth and is a cancer hallmark and an attractive cancer therapeutic target. Our effort toward understanding the action mechanisms, including resistance mechanisms, of osimertinib has led to the identification of a novel and critical role in maintaining c-Myc-dependent downregulation of hTERT, a catalytic subunit of telomerase, and subsequent inhibition of telomerase/telomere and induction of telomere dysfunction in mediating therapeutic efficacy of osimertinib. Consequently, osimertinib combined with the telomere inhibitor, 6-Thio-dG, which is currently tested in a phase II trial, effectively inhibited the growth of osimertinib-resistant tumors, regressed EGFRm NSCLC patient-derived xenografts, and delayed the emergence of acquired resistance to osimertinib, warranting clinical validation of this strategy to manage osimertinib acquired resistance.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 11","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288976","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

SMARCA5-mediated chromatin remodeling is required for germinal center formation. 生殖中心的形成需要SMARCA5介导的染色质重塑。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-11-04 Epub Date: 2024-09-19 DOI: 10.1084/jem.20240433

Liat Stoler-Barak, Dominik Schmiedel, Avital Sarusi-Portuguez, Adi Rogel, Ronnie Blecher-Gonen, Zhana Haimon, Tomas Stopka, Ziv Shulman

{"title":"SMARCA5-mediated chromatin remodeling is required for germinal center formation.","authors":"Liat Stoler-Barak, Dominik Schmiedel, Avital Sarusi-Portuguez, Adi Rogel, Ronnie Blecher-Gonen, Zhana Haimon, Tomas Stopka, Ziv Shulman","doi":"10.1084/jem.20240433","DOIUrl":"10.1084/jem.20240433","url":null,"abstract":"The establishment of long-lasting immunity against pathogens is facilitated by the germinal center (GC) reaction, during which B cells increase their antibody affinity and differentiate into antibody-secreting cells (ASC) and memory cells. These events involve modifications in chromatin packaging that orchestrate the profound restructuring of gene expression networks that determine cell fate. While several chromatin remodelers were implicated in lymphocyte functions, less is known about SMARCA5. Here, using ribosomal pull-down for analyzing translated genes in GC B cells, coupled with functional experiments in mice, we identified SMARCA5 as a key chromatin remodeler in B cells. While the naive B cell compartment remained unaffected following conditional depletion of Smarca5, effective proliferation during B cell activation, immunoglobulin class switching, and as a result GC formation and ASC differentiation were impaired. Single-cell multiomic sequencing analyses revealed that SMARCA5 is crucial for facilitating the transcriptional modifications and genomic accessibility of genes that support B cell activation and differentiation. These findings offer novel insights into the functions of SMARCA5, which can be targeted in various human pathologies.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 11","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288977","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

Mitochondria as a primary determinant of angiogenic modality in pulmonary arterial hypertension. 线粒体是肺动脉高压血管生成模式的主要决定因素。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-11-04 Epub Date: 2024-09-25 DOI: 10.1084/jem.20231568

Maki Niihori, Joel James, Mathews V Varghese, Nolan McClain, Odunayo Susan Lawal, Rohit C Philip, Brenda K Baggett, Dmitry A Goncharov, Vinicio de Jesus Perez, Elena A Goncharova, Ruslan Rafikov, Olga Rafikova

{"title":"Mitochondria as a primary determinant of angiogenic modality in pulmonary arterial hypertension.","authors":"Maki Niihori, Joel James, Mathews V Varghese, Nolan McClain, Odunayo Susan Lawal, Rohit C Philip, Brenda K Baggett, Dmitry A Goncharov, Vinicio de Jesus Perez, Elena A Goncharova, Ruslan Rafikov, Olga Rafikova","doi":"10.1084/jem.20231568","DOIUrl":"10.1084/jem.20231568","url":null,"abstract":"Impaired pulmonary angiogenesis plays a pivotal role in the progression of pulmonary arterial hypertension (PAH) and patient mortality, yet the molecular mechanisms driving this process remain enigmatic. Our study uncovered a striking connection between mitochondrial dysfunction (MD), caused by a humanized mutation in the NFU1 gene, and severely disrupted pulmonary angiogenesis in adult lungs. Restoring the bioavailability of the NFU1 downstream target, lipoic acid (LA), alleviated MD and angiogenic deficiency and rescued the progressive PAH phenotype in the NFU1G206C model. Notably, significant NFU1 expression and signaling insufficiencies were also identified in idiopathic PAH (iPAH) patients' lungs, emphasizing this study's relevance beyond NFU1 mutation cases. The remarkable improvement in mitochondrial function of PAH patient-derived pulmonary artery endothelial cells (PAECs) following LA supplementation introduces LA as a potential therapeutic approach. In conclusion, this study unveils a novel role for MD in dysregulated pulmonary angiogenesis and PAH manifestation, emphasizing the need to correct MD in PAH patients with unrecognized NFU1/LA deficiency.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 11","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347958","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: Precursor central memory versus effector cell fate and naïve CD4+ T cell heterogeneity. 更正：前体中央记忆细胞与效应细胞的命运以及幼稚 CD4+ T 细胞的异质性。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-11-04 Epub Date: 2024-10-30 DOI: 10.1084/jem.2023119310182024c

Deeksha Deep, Herman Gudjonson, Chrysothemis C Brown, Samuel A Rose, Roshan Sharma, Yoselin A Paucar Iza, Seunghee Hong, Saskia Hemmers, Michail Schizas, Zhong-Min Wang, Yuezhou Chen, Duane R Wesemann, Virginia Pascual, Dana Pe'er, Alexander Y Rudensky

引用次数: 0

Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity. 磷脂酰丝氨酸磷脂酶 A1 使 GPR34 依赖性免疫细胞在腹腔内聚集。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-11-04 Epub Date: 2024-10-16 DOI: 10.1084/jem.20240992

Hanson Tam, Ying Xu, Jinping An, Torsten Schöneberg, Angela Schulz, Jagan R Muppidi, Jason G Cyster

{"title":"Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity.","authors":"Hanson Tam, Ying Xu, Jinping An, Torsten Schöneberg, Angela Schulz, Jagan R Muppidi, Jason G Cyster","doi":"10.1084/jem.20240992","DOIUrl":"https://doi.org/10.1084/jem.20240992","url":null,"abstract":"The peritoneal cavity (PerC) is an important site for immune responses to infection and cancer metastasis. Yet few ligand-receptor axes are known to preferentially govern immune cell accumulation in this compartment. GPR34 is a lysophosphatidylserine (lysoPS)-responsive receptor that frequently harbors gain-of-function mutations in mucosa-associated B cell lymphoma. Here, we set out to test the impact of a GPR34 knock-in (KI) allele in the B-lineage. We report that GPR34 KI promotes the PerC accumulation of plasma cells (PC) and memory B cells (MemB). These KI cells migrate robustly to lysoPS ex vivo, and the KI allele synergizes with a Bcl2 transgene to promote MemB but not PC accumulation. Gene expression and labeling studies reveal that GPR34 KI enhances PerC MemB proliferation. Both KI PC and MemB are specifically enriched at the omentum, a visceral adipose tissue containing fibroblasts that express the lysoPS-generating PLA1A enzyme. Adoptive transfer and chimera experiments revealed that KI PC and MemB maintenance in the PerC is dependent on stromal PLA1A. These findings provide in vivo evidence that PLA1A produces lysoPS that can regulate GPR34-mediated immune cell accumulation at the omentum.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 11","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142485925","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

Targeting TNF/TNFR superfamilies in immune-mediated inflammatory diseases. 针对免疫介导的炎症性疾病中的 TNF/TNFR 超家族。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-11-04 Epub Date: 2024-09-19 DOI: 10.1084/jem.20240806

Praveen Krishna Veerasubramanian, Thomas A Wynn, Jie Quan, Fridrik J Karlsson

引用次数: 0

Aberrant pre-mRNA processing in cancer. 癌症中异常的前核糖核酸（pre-mRNA）加工。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-11-04 Epub Date: 2024-09-24 DOI: 10.1084/jem.20230891

Jeetayu Biswas, Leora Boussi, Eytan Stein, Omar Abdel-Wahab

引用次数: 0