Journal of Experimental Medicine最新文献_第3页

A multimorphic variant in ThPOK causes an inborn error of immunity with T cell defects and fibrosis. ThPOK的多形态变异导致先天免疫错误，伴有T细胞缺陷和纤维化。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-08-04 Epub Date: 2025-05-20 DOI: 10.1084/jem.20241174

Maryam Vaseghi-Shanjani, Mehul Sharma, Pariya Yousefi, Simran Samra, Kaitlin U Laverty, Arttu Jolma, Rozita Razavi, Ally H W Yang, Mihai Albu, Liam Golding, Anna F Lee, Ryan Tan, Phillip A Richmond, Marita Bosticardo, Jonathan H Rayment, Connie L Yang, Kyla J Hildebrand, Rae Brager, Michelle K Demos, Yu-Lung Lau, Luigi D Notarangelo, Timothy R Hughes, Catherine M Biggs, Stuart E Turvey

{"title":"A multimorphic variant in ThPOK causes an inborn error of immunity with T cell defects and fibrosis.","authors":"Maryam Vaseghi-Shanjani, Mehul Sharma, Pariya Yousefi, Simran Samra, Kaitlin U Laverty, Arttu Jolma, Rozita Razavi, Ally H W Yang, Mihai Albu, Liam Golding, Anna F Lee, Ryan Tan, Phillip A Richmond, Marita Bosticardo, Jonathan H Rayment, Connie L Yang, Kyla J Hildebrand, Rae Brager, Michelle K Demos, Yu-Lung Lau, Luigi D Notarangelo, Timothy R Hughes, Catherine M Biggs, Stuart E Turvey","doi":"10.1084/jem.20241174","DOIUrl":"10.1084/jem.20241174","url":null,"abstract":"ThPOK is a transcription factor that acts as a master regulator of CD4+ T cell lineage commitment. We report the first human disease caused by a genetic alteration in ThPOK, specifically, a damaging heterozygous de novo variant in ThPOK (NM_001256455.2:c.1080A>C, p.K360N). This patient exhibited the unusual constellation of persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The ThPOKK360N variant displayed abnormal multimorphic activity, interfering with ThPOKWT (antimorph), failing to bind wild-type ThPOK consensus sequences (amorph), and showing novel DNA-binding specificity (neomorph). Single-cell RNA sequencing revealed defects in CD4+ and CD8+ T cell maturation and activation (hypomorph). Recapitulated in lentivirally transduced healthy control T cells and fibroblasts, the transcriptomic analysis showed ThPOKK360N-transduced T cells had impaired TCR activation and ThPOKK360N-transduced fibroblasts with increased profibrotic gene expression. This novel human disease confirms ThPOK's role in CD4+ T cell development but also uncovers novel roles in TCR activation and regulation of fibrotic pathways in fibroblasts.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12091070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110413","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

Expression of Concern: ΔNp73, A Dominant-Negative Inhibitor of Wild-type p53 and TAp73, Is Up-regulated in Human Tumors. 关注表达：ΔNp73，野生型p53和TAp73的显性阴性抑制剂，在人类肿瘤中上调。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-06-27 DOI: 10.1084/jem.2002017906102025e

引用次数: 0

Plasmodium falciparum infection induces T cell tolerance that is associated with decreased disease severity upon re-infection. 恶性疟原虫感染诱导T细胞耐受，这与再次感染后疾病严重程度降低有关。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-04-11 DOI: 10.1084/jem.20241667

Diana Muñoz Sandoval, Florian A Bach, Alasdair Ivens, Adam C Harding, Natasha L Smith, Michalina Mazurczyk, Yrene Themistocleous, Nick J Edwards, Sarah E Silk, Jordan R Barrett, Graeme J M Cowan, Giorgio Napolitani, Nicholas J Savill, Simon J Draper, Angela M Minassian, Wiebke Nahrendorf, Philip J Spence

{"title":"Plasmodium falciparum infection induces T cell tolerance that is associated with decreased disease severity upon re-infection.","authors":"Diana Muñoz Sandoval, Florian A Bach, Alasdair Ivens, Adam C Harding, Natasha L Smith, Michalina Mazurczyk, Yrene Themistocleous, Nick J Edwards, Sarah E Silk, Jordan R Barrett, Graeme J M Cowan, Giorgio Napolitani, Nicholas J Savill, Simon J Draper, Angela M Minassian, Wiebke Nahrendorf, Philip J Spence","doi":"10.1084/jem.20241667","DOIUrl":"https://doi.org/10.1084/jem.20241667","url":null,"abstract":"Immunity to severe malaria is acquired quickly, operates independently of pathogen load, and represents a highly effective form of disease tolerance. The mechanism that underpins tolerance remains unknown. We used a human rechallenge model of falciparum malaria in which healthy adult volunteers were infected three times over a 12 mo period to track the development of disease tolerance in real-time. We found that parasitemia triggered a hardwired innate immune response that led to systemic inflammation, pyrexia, and hallmark symptoms of clinical malaria across the first three infections of life. In contrast, a single infection was sufficient to reprogram T cell activation and reduce the number and diversity of effector cells upon rechallenge. Crucially, this did not silence stem-like memory cells but instead prevented the generation of cytotoxic effectors associated with autoinflammatory disease. Tolerized hosts were thus able to prevent collateral tissue damage in the absence of antiparasite immunity.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023415","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: ICAM-1 controls development and function of ILC2. 更正：ICAM-1控制ILC2的发育和功能。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-06-25 DOI: 10.1084/jem.2017235906182025c

Ai-Hua Lei, Qiang Xiao, Gao-Yu Liu, Kun Shi, Qiong Yang, Xing Li, Yu-Feng Liu, Hai-Kun Wang, Wei-Ping Cai, Yu-Juan Guan, Dmitry I Gabrilovich, Jie Zhou

引用次数: 0

Noncanonical T cell responses are associated with protection from tuberculosis in mice and humans. 在小鼠和人类中，非典型T细胞反应与预防结核病有关。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-04-07 DOI: 10.1084/jem.20241760

Megan K Proulx, Christine D Wiggins, Charlotte J Reames, Claire Wu, Michael C Kiritsy, Ping Xu, Judith C Gallant, Patricia S Grace, Brooke A Fenderson, Clare M Smith, Cecilia S Lindestam Arlehamn, Galit Alter, Douglas A Lauffenburger, Christopher M Sassetti

{"title":"Noncanonical T cell responses are associated with protection from tuberculosis in mice and humans.","authors":"Megan K Proulx, Christine D Wiggins, Charlotte J Reames, Claire Wu, Michael C Kiritsy, Ping Xu, Judith C Gallant, Patricia S Grace, Brooke A Fenderson, Clare M Smith, Cecilia S Lindestam Arlehamn, Galit Alter, Douglas A Lauffenburger, Christopher M Sassetti","doi":"10.1084/jem.20241760","DOIUrl":"10.1084/jem.20241760","url":null,"abstract":"While control of Mycobacterium tuberculosis (Mtb) infection is generally understood to require Th1 cells and IFNγ, infection produces a spectrum of immunological and pathological phenotypes in diverse human populations. By characterizing Mtb infection in mouse strains that model the genetic heterogeneity of an outbred population, we identified strains that control Mtb comparably to a standard IFNγ-dependent mouse model but with substantially lower lung IFNγ levels. We report that these mice have a significantly altered CD4 T cell profile that specifically lacks the terminal effector Th1 subset and that this phenotype is detectable before infection. These mice still require T cells to control bacterial burden but are less dependent on IFNγ signaling. Instead, noncanonical immune features such as Th17-like CD4 and γδT cells correlate with low bacterial burden. We find the same Th17 transcriptional programs are associated with resistance to Mtb infection in humans, implicating specific non-Th1 T cell responses as a common feature of Mtb control across species.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795551","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

Microbiota-centered interventions to boost immune checkpoint blockade therapies. 以微生物群为中心的干预措施促进免疫检查点阻断疗法。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-04-22 DOI: 10.1084/jem.20250378

Andrew A Almonte, Simon Thomas, Laurence Zitvogel

引用次数: 0

IRF7 controls spontaneous autoimmune germinal center and plasma cell checkpoints. IRF7控制自发自身免疫生发中心和浆细胞检查点。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-05-27 DOI: 10.1084/jem.20231882

Adam J Fike, Kristen N Bricker, Michael V Gonzalez, Anju Maharjan, Tien Bui, Keomonyroth Nuon, Scott M Emrich, Julia L Weber, Sara A Luckenbill, Nicholas M Choi, Renan Sauteraud, Dajiang J Liu, Nancy J Olsen, Roberto Caricchio, Mohamed Trebak, Sathi Babu Chodisetti, Ziaur S M Rahman

{"title":"IRF7 controls spontaneous autoimmune germinal center and plasma cell checkpoints.","authors":"Adam J Fike, Kristen N Bricker, Michael V Gonzalez, Anju Maharjan, Tien Bui, Keomonyroth Nuon, Scott M Emrich, Julia L Weber, Sara A Luckenbill, Nicholas M Choi, Renan Sauteraud, Dajiang J Liu, Nancy J Olsen, Roberto Caricchio, Mohamed Trebak, Sathi Babu Chodisetti, Ziaur S M Rahman","doi":"10.1084/jem.20231882","DOIUrl":"10.1084/jem.20231882","url":null,"abstract":"How IRF7 promotes autoimmune B cell responses and systemic autoimmunity is unclear. Analysis of spontaneous SLE-prone mice deficient in IRF7 uncovered the IRF7 role in regulating autoimmune germinal center (GC), plasma cell (PC), and autoantibody responses and disease. IRF7, however, was dispensable for foreign antigen-driven GC, PC, and antibody responses. Competitive bone marrow (BM) chimeras highlighted the importance of IRF7 in hematopoietic cells in spontaneous GC and PC differentiation. Single-cell RNAseq of SLE-prone B cells indicated IRF7-mediated B cell differentiation through GC and PC fates. Mechanistic studies revealed that IRF7 promoted B cell differentiation through GC and PC fates by regulating the transcriptome, translation, and metabolism of SLE-prone B cells. Mixed BM chimeras demonstrated a requirement for B cell-intrinsic IRF7 in IgG autoantibody production but not in the regulation of spontaneous GC and PC responses. Altogether, we delineate previously unknown B cell-intrinsic and -extrinsic mechanisms of IRF7-promoted spontaneous GC and PC responses, loss of tolerance, autoantibody production, and SLE development.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174117","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

Factor XII-driven coagulation traps bacterial infections. 因子十二驱动凝血陷阱细菌感染。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-04-22 DOI: 10.1084/jem.20250049

Katrin F Nickel, Anne Jämsä, Sandra Konrath, Praveen Papareddy, Lynn M Butler, Evi X Stavrou, Maike Frye, Mathias Gelderblom, Bernhard Nieswandt, Sven Hammerschmidt, Heiko Herwald, Thomas Renné

{"title":"Factor XII-driven coagulation traps bacterial infections.","authors":"Katrin F Nickel, Anne Jämsä, Sandra Konrath, Praveen Papareddy, Lynn M Butler, Evi X Stavrou, Maike Frye, Mathias Gelderblom, Bernhard Nieswandt, Sven Hammerschmidt, Heiko Herwald, Thomas Renné","doi":"10.1084/jem.20250049","DOIUrl":"https://doi.org/10.1084/jem.20250049","url":null,"abstract":"Blood coagulation is essential for stopping bleeding but also drives thromboembolic disorders. Factor XII (FXII)-triggered coagulation promotes thrombosis while being dispensable for hemostasis, making it a potential anticoagulant target. However, its physiological role remains unclear. Here, we demonstrate that FXII-driven coagulation enhances innate immunity by trapping pathogens and restricting bacterial infection in mice. Streptococcus pneumoniae infection was more severe in FXII-deficient (F12-/-) mice, with increased pulmonary bacterial burden, systemic spread, and mortality. Similarly, Staphylococcus aureus skin infections and systemic dissemination were exacerbated in F12-/- mice. Reconstitution with human FXII restored bacterial containment. Plasma kallikrein amplifies FXII activation, and its deficiency aggravated S. aureus skin infections, similarly to F12-/- mice. FXII deficiency impaired fibrin deposition in abscess walls, leading to leaky capsules and bacterial escape. Bacterial long-chain polyphosphate activated FXII, triggering fibrin formation. Deficiency in FXII substrate factor XI or FXII/factor XI co-deficiency similarly exacerbated S. aureus infection. The data reveal a protective role for FXII-driven coagulation in host defense, urging caution in developing therapeutic strategies targeting this pathway.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004769","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

Emerging in vivo tools for ILC2 research. 新兴的ILC2体内研究工具。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-05-29 DOI: 10.1084/jem.20250883

Timotheus Y F Halim

引用次数: 0

Sympathetic axonogenesis promotes adenoid cystic carcinoma progression. 交感轴突发生促进腺样囊性癌进展。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-07-07 Epub Date: 2025-04-24 DOI: 10.1084/jem.20242250

Chun-Hao Chen, Boris Reva, Nora Katabi, Avishai Wizel, Hongbo Xu, Alan L Ho, Luc G T Morris, Richard L Bakst, Anuraag S Parikh, Yotam Drier, Sylvie Deborde, Richard J Wong

{"title":"Sympathetic axonogenesis promotes adenoid cystic carcinoma progression.","authors":"Chun-Hao Chen, Boris Reva, Nora Katabi, Avishai Wizel, Hongbo Xu, Alan L Ho, Luc G T Morris, Richard L Bakst, Anuraag S Parikh, Yotam Drier, Sylvie Deborde, Richard J Wong","doi":"10.1084/jem.20242250","DOIUrl":"https://doi.org/10.1084/jem.20242250","url":null,"abstract":"Nerves are integral to the adenoid cystic carcinoma (ACC) microenvironment. The strong association of ACC with perineural invasion (PNI) is considered a hallmark of this disease. In human salivary ACC, we identify intratumoral, small-caliber, disorganized sympathetic nerves not observed in other salivary neoplasms. Norepinephrine or sympathetic ganglia explants enhance ACC proliferation in vitro. Two novel orthotopic ACC patient-derived xenograft (PDX) models recapitulate ACC morphology and demonstrate sympathetic innervation. Pharmacologic or surgical blockade of sympathetic nerves decreases ACC PDX growth. Bulk RNA sequencing of salivary ACC reveals correlations between noradrenergic nerve development signatures and worse patient survival. Metastatic ACC foci exhibit lower nerve signature gene expression levels than primary ACC. Sympathetic innervation in ACC is distinct from PNI and reflects tumor axonogenesis driven by noradrenergic neural development programs. These programs support ACC progression, are associated with poor prognosis, and may be inhibited as a therapeutic strategy.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971326","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