Journal of Experimental Medicine最新文献_第8页

"What's in a name?" Clarifying the identity of RORγt+ antigen-presenting cells. “名字有什么用？”澄清RORγt+抗原呈递细胞的身份。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-08-04 Epub Date: 2025-05-15 DOI: 10.1084/jem.20250760

Feiya Ou, Kenneth M Murphy

引用次数: 0

RORγt eTACs mediate oral tolerance and Treg induction. r γ - t eTACs介导口服耐受性和Treg诱导。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-08-04 Epub Date: 2025-04-29 DOI: 10.1084/jem.20250573

Im-Hong Sun, Anita E Qualls, Han S Yin, Jiaxi Wang, Matthew P Arvedson, Joe Germino, Nolan K Horner, Sheng Zhong, Juan Du, Martin Valdearcos, Vasilis Ntranos, Richard M Locksley, Roberto R Ricardo-Gonzalez, James M Gardner

{"title":"RORγt eTACs mediate oral tolerance and Treg induction.","authors":"Im-Hong Sun, Anita E Qualls, Han S Yin, Jiaxi Wang, Matthew P Arvedson, Joe Germino, Nolan K Horner, Sheng Zhong, Juan Du, Martin Valdearcos, Vasilis Ntranos, Richard M Locksley, Roberto R Ricardo-Gonzalez, James M Gardner","doi":"10.1084/jem.20250573","DOIUrl":"10.1084/jem.20250573","url":null,"abstract":"The immune system must distinguish pathogens from innocuous dietary antigens, but the precise mechanisms and cellular actors remain unclear. Here, we demonstrate that RORγt-lineage APCs are required for oral tolerance. Using lineage tracing and single-cell sequencing, we show these APCs consist of three principal populations: type 3 innate lymphoid cells (ILC3s), RORγt-lineage dendritic cells, and cells expressing Aire called RORγt eTACs (R-eTACs)-also known as Janus or Thetis cells. We show that R-eTACs, but not ILC3s, are required for oral tolerance induction. We find R-eTACs are of probable myeloid origin and uniquely express integrin β8 (Itgb8). Both MHCII and Itgb8 expression in RORγt-lineage cells are necessary to induce food-specific regulatory T cells. Mice lacking R-eTACs or with deletion of MHCII or Itgb8 in the RORγt lineage fail to generate Tregs and instead develop a T-follicular helper response with elevated antigen-specific antibodies. These findings establish R-eTACs as critical mediators of oral tolerance and suggest novel cellular targets to modulate immune tolerance.","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/PMC12039581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022562","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

A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain. 去泛素酶USP5的病理性错义突变导致对疼痛不敏感。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-08-04 Epub Date: 2025-05-16 DOI: 10.1084/jem.20241877

Flavia T T Antunes, Maria A Gandini, Agustin Garcia-Caballero, Sun Huang, Md Yousof Ali, Eder Gambeta, Ivana A Souza, Erika K Harding, Laurent Ferron, Asbjorg Stray-Pedersen, Vinicius M Gadotti, Gerald W Zamponi

{"title":"A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain.","authors":"Flavia T T Antunes, Maria A Gandini, Agustin Garcia-Caballero, Sun Huang, Md Yousof Ali, Eder Gambeta, Ivana A Souza, Erika K Harding, Laurent Ferron, Asbjorg Stray-Pedersen, Vinicius M Gadotti, Gerald W Zamponi","doi":"10.1084/jem.20241877","DOIUrl":"10.1084/jem.20241877","url":null,"abstract":"Cav3.2 T-type calcium channels and their dysregulation by the deubiquitinase USP5 contribute to development of inflammatory and neuropathic pain. We report on a pediatric patient with a de novo heterozygous missense mutation R24W in USP5 who exhibits pain insensitivity. We created a CRISPR knock-in mouse harboring this mutation and performed detailed behavioral analyses in acute and chronic pain models. Heterozygous R24W mice of both sexes are resistant to acute pain and to thermal hypersensitivity in chronic inflammatory and neuropathic pain models. In contrast, only male R24W mice confer resistance to development of mechanical hypersensitivity. R24W mice lack upregulation of Cav3.2 and USP5 that is normally observed with CFA-induced inflammation. Moreover, mutant USP5 exhibits a dramatic reduction in enzymatic activity but stronger interactions with Cav3.2. Hence, R24W mutant USP5 is a critical regulator of chronic and acute pain states in humans by acting as a dominant-negative regulator of Cav3.2. Our data validate USP5 as a potential therapeutic target for chronic pain in humans.","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/PMC12083249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078343","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

BCOR and ZC3H12A suppress a core stemness program in exhausted CD8+ T cells. BCOR和ZC3H12A抑制枯竭的CD8+ T细胞的核心干细胞程序。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-08-04 Epub Date: 2025-05-06 DOI: 10.1084/jem.20241133

Jing Xu, Zeran Jia, Xiaocui Zhao, Lixia Wang, Gang Jin, Zhuoyang Li, Na Yin, Yinqing Li, Min Peng

{"title":"BCOR and ZC3H12A suppress a core stemness program in exhausted CD8+ T cells.","authors":"Jing Xu, Zeran Jia, Xiaocui Zhao, Lixia Wang, Gang Jin, Zhuoyang Li, Na Yin, Yinqing Li, Min Peng","doi":"10.1084/jem.20241133","DOIUrl":"10.1084/jem.20241133","url":null,"abstract":"In chronic viral infections, sustained CD8+ T cell response relies on TCF1+ precursor-exhausted T cells (TPEX) exhibiting stem-like properties. TPEX self-renew and respond to PD-1 blockade, underscoring their paramount importance. However, strategies for effectively augmenting TPEX remain limited. Here, we demonstrate that ZC3H12A deficiency initiates a stemness program in TPEX but also increases cell death, whereas BCOR deficiency predominantly promotes TPEX proliferation. Consequently, co-targeting of both BCOR and ZC3H12A imparts exceptional stemness and functionality to TPEX, thereby enhancing viral control. Mechanistically, BCOR and ZC3H12A collaboratively suppress a core stemness program in TPEX characterized by heightened expression of ∼216 factors. While TCF1 plays a role, this core stemness program relies on novel factors, including PDZK1IP1, IFIT3, PIM2, LTB, and POU2F2. Crucially, overexpressing POU2F2 robustly boosts TPEX and enhances antiviral immunity. Thus, a core stemness program exists in exhausted T cells, jointly repressed by BCOR and ZC3H12A, robustly controlling TPEX differentiation and providing new targets for addressing T cell exhaustion.","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/PMC12054362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021147","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

Gut dysbiosis from high-salt diet promotes glioma via propionate-mediated TGF-β activation. 高盐饮食引起的肠道生态失调通过丙酸介导的TGF-β激活促进胶质瘤。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-08-04 Epub Date: 2025-05-22 DOI: 10.1084/jem.20241135

Chae Won Kim, Hyun-Jin Kim, In Kang, Keun Bon Ku, Yumin Kim, Jang Hyun Park, Juhee Lim, Byeong Hoon Kang, Won Hyung Park, Jeongwoo La, Sungwoo Chang, Inju Hwang, Minji Kim, Stephen Ahn, Heung Kyu Lee

{"title":"Gut dysbiosis from high-salt diet promotes glioma via propionate-mediated TGF-β activation.","authors":"Chae Won Kim, Hyun-Jin Kim, In Kang, Keun Bon Ku, Yumin Kim, Jang Hyun Park, Juhee Lim, Byeong Hoon Kang, Won Hyung Park, Jeongwoo La, Sungwoo Chang, Inju Hwang, Minji Kim, Stephen Ahn, Heung Kyu Lee","doi":"10.1084/jem.20241135","DOIUrl":"10.1084/jem.20241135","url":null,"abstract":"The purpose of this study is to investigate the impact of a high-salt diet (HSD), which is commonly found in Western countries, on the progression of glioma. Our research shows that the alterations in gut microbiota caused by an HSD facilitated the development of glioma. Mice fed an HSD have elevated levels of intestinal propionate, which accelerated the growth of glioma cells. We also find that propionate supplementation enhanced the response of glioma cells to low oxygen levels. Moreover, we identify a link between TGF-β signaling, response to low oxygen levels, and invasion-related pathways. Propionate treatment increases the expression of HIF-1α, leading to an increase in TGF-β1 production. Additionally, propionate treatment promotes glioma cell invasion through TGF-β signaling. Our findings suggest that an HSD-induced increase in propionate plays a crucial role in glioma progression by facilitating invasion through the hypoxic response and TGF-β signaling pathways, thereby establishing a significant connection between gut microbiota and the progression of glioma.","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/PMC12097148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119809","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

Lymphatic chain gradients regulate the magnitude and heterogeneity of T cell responses to vaccination. 淋巴链梯度调节T细胞对疫苗反应的大小和异质性。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-08-04 Epub Date: 2025-04-30 DOI: 10.1084/jem.20241311

Michael T Conlon, Jessica Y Huang, Michael Y Gerner

{"title":"Lymphatic chain gradients regulate the magnitude and heterogeneity of T cell responses to vaccination.","authors":"Michael T Conlon, Jessica Y Huang, Michael Y Gerner","doi":"10.1084/jem.20241311","DOIUrl":"10.1084/jem.20241311","url":null,"abstract":"Upon activation, T cells proliferate and differentiate into diverse populations, including highly differentiated effector and memory precursor subsets. Initial diversification is influenced by signals sensed during T cell priming within lymphoid tissues. However, the rules governing how cellular heterogeneity is spatially encoded in vivo remain unclear. Here, we show that immunization establishes concentration gradients of antigens and inflammation across interconnected chains of draining lymph nodes (IC-LNs). While T cells are activated at all sites, individual IC-LNs elicit divergent responses: proximal IC-LNs favor the generation of effector cells, whereas distal IC-LNs promote formation of central memory precursor cells. Although both proximal and distal sites contribute to anamnestic responses, T cells from proximal IC-LNs preferentially provide early effector responses at inflamed tissues. Conversely, T cells from distal IC-LNs demonstrate an enhanced capacity to generate long-lasting responses to chronic antigens in cancer settings, including after checkpoint blockade therapy. Therefore, formation of spatial gradients across lymphatic chains following vaccination regulates the magnitude, heterogeneity, and longevity of T cell responses.","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/PMC12042774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024329","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

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

HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection. 在慢性病毒感染期间，HDAC1控制效应样CD8+ T细胞的产生和维持。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-08-04 Epub Date: 2025-06-04 DOI: 10.1084/jem.20240829

Ramona Rica, Monika Waldherr, Emi Miyakoda, Ana Patricia Kutschat, Marlene Schülein, Jing Zhang, Ricardo Alfredo Orbegozo-Medina, Lisa Sandner, Valentina Stolz, Darina Waltenberger, Thomas Krausgruber, Christoph Bock, Nicole Boucheron, Davide Seruggia, Wilfried Ellmeier, Shinya Sakaguchi

{"title":"HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection.","authors":"Ramona Rica, Monika Waldherr, Emi Miyakoda, Ana Patricia Kutschat, Marlene Schülein, Jing Zhang, Ricardo Alfredo Orbegozo-Medina, Lisa Sandner, Valentina Stolz, Darina Waltenberger, Thomas Krausgruber, Christoph Bock, Nicole Boucheron, Davide Seruggia, Wilfried Ellmeier, Shinya Sakaguchi","doi":"10.1084/jem.20240829","DOIUrl":"10.1084/jem.20240829","url":null,"abstract":"CD8+ T cell exhaustion is a complex process involving the differentiation of persistently activated CD8+ T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+ Tex cells in a CD8+ T cell-intrinsic manner. Deletion of HDAC1 led to expansion of an alternative Tex subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 bound to and facilitated an open chromatin state of effector-like signature gene loci in progenitor Tex cells, thereby priming cell fate specification toward the CX3CR1+ Tex subset. Our study uncovers a selective role for HDAC1 in CX3CR1+ Tex subset differentiation, which is essential for controlling viral load during chronic infection.","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/PMC12135962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215929","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

Costimulatory connections: CARMIL2 and CD28. 共刺激连接：CARMIL2和CD28。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-08-04 Epub Date: 2025-06-20 DOI: 10.1084/jem.20250896

Lawrence P Kane

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