JCI insight最新文献_第8页

Multiomic analysis identifies T cell subsets and mechanisms of epithelial interaction in idiopathic pulmonary fibrosis. 多组学分析确定特发性肺纤维化中T细胞亚群和上皮相互作用机制。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.203080

Ana Pm Serezani, Julia Mr Bazzano, Bruno D Pascoalino, Ludmilla da Silva, Abigail J Dietrich, Chase J Taylor, Taylor Sherrill, Annika Vannan, Carla L Calvi, Paula I Gonzalez-Ericsson, Erin M Wilfong, Matthew Bacchetta, Ciara M Shaver, Lorraine B Ware, Margaret L Salisbury, Luc Van Kaer, Nicholas E Banovich, Jonathan A Kropski, Timothy S Blackwell

{"title":"Multiomic analysis identifies T cell subsets and mechanisms of epithelial interaction in idiopathic pulmonary fibrosis.","authors":"Ana Pm Serezani, Julia Mr Bazzano, Bruno D Pascoalino, Ludmilla da Silva, Abigail J Dietrich, Chase J Taylor, Taylor Sherrill, Annika Vannan, Carla L Calvi, Paula I Gonzalez-Ericsson, Erin M Wilfong, Matthew Bacchetta, Ciara M Shaver, Lorraine B Ware, Margaret L Salisbury, Luc Van Kaer, Nicholas E Banovich, Jonathan A Kropski, Timothy S Blackwell","doi":"10.1172/jci.insight.203080","DOIUrl":"10.1172/jci.insight.203080","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and respiratory failure. While T cells are elevated in IPF lungs, their contributions to fibrosis beyond inflammation remain poorly understood. Here, we performed multiplex imaging and single-cell RNA and protein profiling on about 90,000 CD3+ T cells from control and fibrotic lungs, revealing 11 distinct subsets of CD4+ and CD8+ T cells, including a rare CD56+ regulatory T cell. In addition to increased T cell numbers in severely fibrotic lungs compared with non-diseased controls, we observed CD4+ and CD8+ T cells localized near epithelial cells and in niches of abnormal epithelium. CXCR4/MIF signaling emerged as a central axis mediating T cell-epithelial interactions, while epidermal growth factor receptor (EGFR) and TGF-β pathways dominated in multiple T cell subsets. Our findings support the concept that T cells in IPF adopt nonclassical activation patterns that are driven by epithelial interactions within the fibrotic microenvironment. These studies provide a foundation for exploring alternative therapeutic strategies in IPF lungs by modulating T cell behavior and communication networks.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905638","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

Noncoding RNA TY1 reverses fibrosis in systemic sclerosis by attenuating the cGAS/STING pathway. 非编码RNA TY1通过减弱cGAS/STING通路逆转系统性硬化症中的纤维化。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.197716

Xaviar M Jones, Salwa Soussi, Alessandra Ciullo, Kara Tsi, Weixin Liu, Liang Li, Mario Fournier, Thassio Mesquita, Alberto M Marchevsky, Nunzio Bottini, Francesco Boin, Ahmed Ge Ibrahim, Eduardo Marbán

{"title":"Noncoding RNA TY1 reverses fibrosis in systemic sclerosis by attenuating the cGAS/STING pathway.","authors":"Xaviar M Jones, Salwa Soussi, Alessandra Ciullo, Kara Tsi, Weixin Liu, Liang Li, Mario Fournier, Thassio Mesquita, Alberto M Marchevsky, Nunzio Bottini, Francesco Boin, Ahmed Ge Ibrahim, Eduardo Marbán","doi":"10.1172/jci.insight.197716","DOIUrl":"10.1172/jci.insight.197716","url":null,"abstract":"DNA damage and the cGAS/STING innate immunity pathway have been associated with fibrosis in systemic sclerosis (SSc), but a cause-and-effect role has not been established. Here we report the effects of TY1, a noncoding RNA drug of the exomer class that suppresses DNA damage and thereby inhibits cGAS/STING, in human SSc cells and in 2 preclinical models of SSc. Macrophages from patients with SSc exhibited high levels of phosphorylated DNA damage, cGAS, 2'3'-cGAMP, STING, and IFNs, all of which decreased after exposure to TY1. In mice that had been injected s.c. with bleomycin to model SSc, exercise tolerance, cardiac function, lung hydroxyproline, and skin thickness reverted to normal levels after oral administration of TY1. Similar therapeutic benefits were evident in the genetic tsk-1 mouse model of SSc. TY1 attenuated fibrosis and/or fibrotic gene expression in both mouse models of SSc and in human SSc skin fibroblasts. Our findings support the hypothesis that cGAS/STING, activated by DNA damage, is a key driver of fibrosis in SSc.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905800","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

Glutamine-dependent biosynthetic pathways fuel autoreactive T and B cells in Foxp3 deficiency-mediated disease. 谷氨酰胺依赖的生物合成途径在Foxp3缺陷介导的疾病中为自身反应性T和B细胞提供燃料。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.200076

Mohammad Adeel Zafar, Charlotte N Hill Machado, Jyotirmaya Behera, Yuelin Zhong, Xiao Li, Shakchhi Joshi, Yassine El Fazaa, Virginia Camacho, Peter Georgiev, Kiran Kurmi, Marcia Haigis, Louis-Marie Charbonnier

{"title":"Glutamine-dependent biosynthetic pathways fuel autoreactive T and B cells in Foxp3 deficiency-mediated disease.","authors":"Mohammad Adeel Zafar, Charlotte N Hill Machado, Jyotirmaya Behera, Yuelin Zhong, Xiao Li, Shakchhi Joshi, Yassine El Fazaa, Virginia Camacho, Peter Georgiev, Kiran Kurmi, Marcia Haigis, Louis-Marie Charbonnier","doi":"10.1172/jci.insight.200076","DOIUrl":"10.1172/jci.insight.200076","url":null,"abstract":"Foxp3 deficiency causes a profound loss of immune tolerance, unleashing autoreactive T and B cells, lymphoproliferation, cytokine-driven inflammation, and autoantibody production. This autoimmune pathology is fueled by increased glutamine usage, but it remains unresolved whether glutamine is necessary to produce energy or for intermediate metabolite biosynthesis responsible for immunomodulation. Here, we demonstrate that glutamine utilization for biosynthetic pathways supported autoimmune inflammation in the settings of Foxp3 deficiency and dextran sodium sulfate-induced colitis. By employing a model of autoimmunity driven by Treg-specific loss of Foxp3, we showed that this effect is independent of pathogenic Foxp3-deficient Treg reprogramming. Mechanistically, glutamine biosynthetic pathways sustained conventional T cell activation and proinflammatory cytokine production by preventing inosine accumulation and signaling, thus implicating adenosine pathway modulation in autoreactive T cell dysregulation. Conversely, autoreactive B cell activation and autoantibody production relied on glutamine-dependent asparagine availability, which we identified as a targetable vulnerability for autoantibody formation. These findings highlighted glutamine-driven biosynthetic processes as critical drivers of autoimmunity and revealed distinct metabolic vulnerabilities in autoreactive T and B cells that could be targeted for therapeutic intervention.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906276","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 familial case of FLAD1 protein deficiency associated with impaired adrenal steroidogenesis. FLAD1蛋白缺乏与肾上腺类固醇生成受损相关的家族性病例。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.198799

Olga A Averina, Natalia Yu Kalinchenko, Vitaly A Ioutsi, Andrey V Pirogov, Alexander V Bogachev, Oleg A Permyakov, Vitaly S Buev, Ekaterina A Guseva, Anastasia V Priymak, Olga A Bazhanova, Mariia A Emelianova, Olga O Grigoryeva, Galina V Baydakova, Maxim A Abakumov, Vasily N Manskikh, Olga A Dontsova, Petr V Sergiev, Anatoly N Tiulpakov

{"title":"A familial case of FLAD1 protein deficiency associated with impaired adrenal steroidogenesis.","authors":"Olga A Averina, Natalia Yu Kalinchenko, Vitaly A Ioutsi, Andrey V Pirogov, Alexander V Bogachev, Oleg A Permyakov, Vitaly S Buev, Ekaterina A Guseva, Anastasia V Priymak, Olga A Bazhanova, Mariia A Emelianova, Olga O Grigoryeva, Galina V Baydakova, Maxim A Abakumov, Vasily N Manskikh, Olga A Dontsova, Petr V Sergiev, Anatoly N Tiulpakov","doi":"10.1172/jci.insight.198799","DOIUrl":"10.1172/jci.insight.198799","url":null,"abstract":"The FLAD1 gene codes for flavin adenine dinucleotide (FAD) synthase. FAD is a cofactor for many redox enzymes involved in vital processes from respiration to signal transduction. In this work, we described a clinical case of 2 siblings carrying compound heterozygous mutations in the FLAD1 gene resulting in the substitutions A418V and R542* at the protein level. The patients demonstrate adrenal insufficiency, which has not previously been associated with FLAD1 protein defects. To verify that adrenal insufficiency is caused by FLAD1 mutations, we created a personalized mouse model carrying the mutations found in the patients. The mutation in the FLAD1 gene, leading to the A418V substitution, appeared viable in the homozygous state, with minimal difference from the WT. The FLAD1 gene mutation leading to the R542* truncation is lethal when homozygous. The mouse model of the compound heterozygous FLAD1A418V/R542* mutations recapitulated the physiological, biochemical, and endocrine manifestations of FLAD1 mutations in patients. The mouse model created demonstrates the causal effect of FLAD1 mutations on the described pathology and potentially paves the way for understanding the disease's molecular mechanism and developing better therapies.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906240","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

Specificity, frequency, and phenotype of citrullinated-specific T cells vary with disease activity in rheumatoid arthritis. 在类风湿性关节炎中，瓜氨酸化特异性T细胞的特异性、频率和表型随疾病活动性而变化。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.202159

Cliff Rims, Hannah A DeBerg, Sylvia E Posso, Virginia S Muir, Hannes Uchtenhagen, Anne M Hocking, Heather Bukiri, Jeffrey Carlin, Bernard Ng, Peter S Linsley, Eddie A James, Jane H Buckner

{"title":"Specificity, frequency, and phenotype of citrullinated-specific T cells vary with disease activity in rheumatoid arthritis.","authors":"Cliff Rims, Hannah A DeBerg, Sylvia E Posso, Virginia S Muir, Hannes Uchtenhagen, Anne M Hocking, Heather Bukiri, Jeffrey Carlin, Bernard Ng, Peter S Linsley, Eddie A James, Jane H Buckner","doi":"10.1172/jci.insight.202159","DOIUrl":"10.1172/jci.insight.202159","url":null,"abstract":"In rheumatoid arthritis (RA), CD4+ T cells specific for citrullinated antigens (cit-antigens) are key drivers of disease, but knowledge about epitopes and phenotypes remains limited. We characterized the frequency and phenotype of cit-specific CD4+ T cells in peripheral blood using HLA class II tetramers combined with computational analysis of phenotypic clusters to simultaneously detect peptides derived from 5 cit-antigens (aggrecan, vimentin, fibrinogen, cartilage intermediate layer protein, and α-enolase) previously implicated in RA pathogenesis. In a cross-sectional cohort, cit-aggrecan-, cit-vimentin-, and cit-fibrinogen-specific T cells were more frequent in participants with RA than healthy volunteers, associated with active disease, and had Th1-like and stem-like lineages in RA. In a longitudinal cohort investigating response to therapy, the frequency of cit-aggrecan-, cit-vimentin-, and cit-fibrinogen-specific CD4+ T cells was significantly higher at baseline and further elevated in responders. Furthermore, the frequency of cit-specific Th1-like cells in responders decreased over time. In contrast, the frequency of Th1-like cells in non-responders increased over time. Collectively, these findings demonstrate that cit-specific CD4+ T cells are expanded in RA and target a broad number of antigens across a breadth of phenotypes. Furthermore, the predominant antigen specificities associate with disease activity and exhibit dynamic changes in phenotype that reflect response to therapy.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905750","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

α-Ketoglutarate accelerates cutaneous wound healing through modulating the epithelial-fibroblast niche. α-酮戊二酸通过调节上皮成纤维细胞生态位加速皮肤伤口愈合。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.201852

Yuhan Li, Weimin Lin, Denghao Huang, Yueying Wang, Yimeng Cai, Jie Xiang, Linfeng Liu, Xinxing Shuai, Qi Yin, Shuang Jiang, Malcolm Xing, Yuan Wang, Leixiao Yu, Quan Yuan

{"title":"α-Ketoglutarate accelerates cutaneous wound healing through modulating the epithelial-fibroblast niche.","authors":"Yuhan Li, Weimin Lin, Denghao Huang, Yueying Wang, Yimeng Cai, Jie Xiang, Linfeng Liu, Xinxing Shuai, Qi Yin, Shuang Jiang, Malcolm Xing, Yuan Wang, Leixiao Yu, Quan Yuan","doi":"10.1172/jci.insight.201852","DOIUrl":"10.1172/jci.insight.201852","url":null,"abstract":"Wound healing is a highly dynamic and metabolically demanding process. However, the primary drivers of metabolic alterations involved in this process remain incompletely understood. Here, we employed multiomics profiling of clinical samples to investigate metabolic alterations during wound healing. Our analyses revealed significant activation of the TCA cycle and identified α-ketoglutarate (αKG) as a central regulator orchestrating the reparative phase. Systemic administration of αKG promoted wound closure and re-epithelialization, characterized by enhanced neo-tissue formation with an extended epithelial tongue. Mechanistically, αKG promoted cell proliferation via the cell cycle pathway and enhanced fibroblast-derived TGF-β signaling to induce epithelial-mesenchymal transition-like programs in epithelial cells. To address the spatial metabolic heterogeneity, we developed a transdermal MN platform based on gelatin methacryloyl for localized αKG delivery, further accelerating tissue repair. Collectively, these findings identify αKG as a metabolic driver of wound repair, reveal its dual role in modulating the epithelial-fibroblast microenvironment, and introduce a targeted bioengineering strategy with translational potential for both acute and chronic wound management.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905788","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

Previous malaria exposure attenuates monocyte-driven inflammation and correlates with modulation of the B cell response. 先前的疟疾暴露会减弱单核细胞驱动的炎症，并与B细胞反应的调节相关。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.199206

Maximilian Julius Lautenbach, Pengjun Xi, Linn Kleberg, Alan-Dine Courey-Ghaouzi, Maia Serene Gower, Carolina Sousa Silva, Felicia Chammas, Anna Färnert, Christopher Sundling

{"title":"Previous malaria exposure attenuates monocyte-driven inflammation and correlates with modulation of the B cell response.","authors":"Maximilian Julius Lautenbach, Pengjun Xi, Linn Kleberg, Alan-Dine Courey-Ghaouzi, Maia Serene Gower, Carolina Sousa Silva, Felicia Chammas, Anna Färnert, Christopher Sundling","doi":"10.1172/jci.insight.199206","DOIUrl":"https://doi.org/10.1172/jci.insight.199206","url":null,"abstract":"Clinical immunity to malaria develops after repeated malaria episodes. In this process, the inflammatory response is modulated to respond less vigorously upon reinfection. Monocytes are a major source of pro-inflammatory mediators during blood-stage infection and are known to adapt to repeated pathogen exposure. Here, we investigated the impact of previous malaria exposure on monocytes during blood-stage malaria by comparing the response in previously exposed and primary infected individuals. We observed reduced levels of several proinflammatory chemokines in previously exposed individuals, linked to changes in monocytes. Similarly, BAFF levels were lower in these individuals and associated with modulation of monocyte and dendritic cells. This affected the BAFF-BAFF-R axis, crucial for B cell responses, correlating with increasing parasite-specific antibody levels. Collectively, we present insights into how previous malaria exposure shapes monocyte responses during acute malaria and how these in turn correlate with modulation of the B cell compartment and humoral immune response. .","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912103","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

SMURF2 inhibits autophagic control of Mycobacterium tuberculosis in macrophages. SMURF2抑制结核分枝杆菌巨噬细胞的自噬控制。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.199853

Priscila C Campos, Kathryn C Rahlwes, Victoria A Ektnitphong, Beatriz Rs Dias, Kubra F Naqvi, Samuel Alvarez-Arguedas, Michael U Shiloh

{"title":"SMURF2 inhibits autophagic control of Mycobacterium tuberculosis in macrophages.","authors":"Priscila C Campos, Kathryn C Rahlwes, Victoria A Ektnitphong, Beatriz Rs Dias, Kubra F Naqvi, Samuel Alvarez-Arguedas, Michael U Shiloh","doi":"10.1172/jci.insight.199853","DOIUrl":"10.1172/jci.insight.199853","url":null,"abstract":"Autophagy is a critical host defense mechanism that restricts intracellular pathogens such as Mycobacterium tuberculosis (Mtb). A key step in this process is the ubiquitination of Mtb or Mtb-associated structures. The E3 ligase SMURF1 catalyzes K48-linked ubiquitination, promoting bacterial clearance. However, the function of its homolog, SMURF2, in host defense remains undefined. Here, we demonstrate that Smurf2 deletion in murine macrophages increases SMURF1 levels, enhances LC3B lipidation, augments K48 ubiquitination of Mtb-associated structures, and reduces intracellular Mtb replication. These effects are reversed by Smurf1 deletion, supporting a role for SMURF1 in SMURF2-dependent control of Mtb. Mice with myeloid-specific Smurf2 deletion exhibit modestly prolonged survival following aerosol Mtb infection. In human macrophages, SMURF2 knockdown or its pharmacological inhibition with the HECT E3-ligase inhibitor Heclin reduces Mtb replication. Together, our findings identify SMURF2 as a negative regulator of macrophage control of Mtb and support further investigation of SMURF2 as a potential target for host-directed therapy in tuberculosis.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912035","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

Impaired regulation by purinergic signaling axis contributes to CD8+ T cell dysregulation in STAT3 gain of function. 嘌呤能信号轴的调节受损有助于CD8+ T细胞在STAT3功能获得中的失调。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-08 DOI: 10.1172/jci.insight.202959

Jose S Campos Duran, Montana S Knight, Samir U Sayed, Megan C Dalalo, Andrea A Mauracher, Peyton Conrey, Aaron B Schultz, Ceire A Hay, Robert B Lindell, Ilona Neale, Kyle Yeakle, Eric D Abrams, Erica G Schmitt, Martin A Thelin, Christian A Howard, Sara Bluestein, Christine M Seroogy, Tamara C Pozos, Akaluck Thatayatikom, Ingrid S Lundgren, Amelie Gauthier, Scott W Canna, Helen C Su, Michael D Keller, Ottavia M Delmonte, Lisa R Forbes Satter, Steven M Holland, Jenna Re Bergerson, Jennifer W Leiding, Neil Romberg, Will Bailis, Christopher A Hunter, Alexandra F Freeman, Alejandro V Villarino, Mark S Anderson, Megan A Cooper, Tiphanie P Vogel, Sarah E Henrickson

{"title":"Impaired regulation by purinergic signaling axis contributes to CD8+ T cell dysregulation in STAT3 gain of function.","authors":"Jose S Campos Duran, Montana S Knight, Samir U Sayed, Megan C Dalalo, Andrea A Mauracher, Peyton Conrey, Aaron B Schultz, Ceire A Hay, Robert B Lindell, Ilona Neale, Kyle Yeakle, Eric D Abrams, Erica G Schmitt, Martin A Thelin, Christian A Howard, Sara Bluestein, Christine M Seroogy, Tamara C Pozos, Akaluck Thatayatikom, Ingrid S Lundgren, Amelie Gauthier, Scott W Canna, Helen C Su, Michael D Keller, Ottavia M Delmonte, Lisa R Forbes Satter, Steven M Holland, Jenna Re Bergerson, Jennifer W Leiding, Neil Romberg, Will Bailis, Christopher A Hunter, Alexandra F Freeman, Alejandro V Villarino, Mark S Anderson, Megan A Cooper, Tiphanie P Vogel, Sarah E Henrickson","doi":"10.1172/jci.insight.202959","DOIUrl":"10.1172/jci.insight.202959","url":null,"abstract":"Gain-of-function (GOF) variants in STAT3 cause a complex disorder characterized by early-onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity, though the exact mechanisms remain poorly understood. Here, we found that in patients with STAT3 GOF, CD8+ T cells exist in an activated state. Functional assessment revealed that naive CD8+ T cells have an increased capacity for IFN-γ and TNF-α production, with type I and type II IFN transcriptional signatures. Evaluation of immunoregulatory pathways revealed dysregulation of the purinergic signaling axis in CD8+ T cells: CD39 was increased, whereas downstream purinergic family members, CD73 and the adenosine receptor A2AR, were downregulated, impairing the potential to produce or sense immunosuppressive adenosine. Evaluation of the impact of precision therapy, in the form of JAK inhibition, at a cellular and functional level revealed partial normalization of CD8+ T cell dysregulation in patients, including aberrant cytokine production. Our study suggests that a dysregulated purinergic signaling axis plays a key role in CD8+ T cell dysregulation in STAT3 GOF and may have implications for other rare monogenic immune disorders and common inflammatory disorders.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 17","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905559","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

Predoctoral grant writing among physician-scientist trainees: a national survey of barriers and facilitators of success. 医师-科学家培训生的博士前拨款写作：一项关于成功障碍和促进因素的全国性调查。

IF 6.8 1区医学

JCI insight Pub Date : 2026-09-01 eCollection Date: 2026-10-08 DOI: 10.1172/jci.insight.208965

Brian J Thomas, Tiger Zhang, Daniel C Brock, Timothy J Ley, W David Arnold, Cynthia Y Tang

{"title":"Predoctoral grant writing among physician-scientist trainees: a national survey of barriers and facilitators of success.","authors":"Brian J Thomas, Tiger Zhang, Daniel C Brock, Timothy J Ley, W David Arnold, Cynthia Y Tang","doi":"10.1172/jci.insight.208965","DOIUrl":"10.1172/jci.insight.208965","url":null,"abstract":"Effective grant writing is an essential skill for physician-scientists to achieve academic independence and long-term career success. Previous studies have established that receiving an NIH F30 or F31 during predoctoral training is correlated with success in subsequent training stages and contributes to the retention of physician-scientists in academia. However, many trainees experience challenges in predoctoral grant writing that prevent them from submitting a grant or developing a well-rounded application. Identifying and addressing such barriers and obstacles remains crucial; however, limitations in NIH public reporting exclude data on prospective applicants and applicants who were not awarded grants. In this study, we employed a national survey of trainees to identify perceived needs and barriers to grant writing as well as factors associated with NIH predoctoral grant funding success. We found that limited mentor and sponsor support of the development of quality applications, constrained eligibility timelines, and limited available awards were prominent barriers to submission, while access to previously funded applications was the most valued resource among respondents. Using these findings, we highlight opportunities for interventions at the federal, institutional, applicant, and medical and scientific society levels to improve predoctoral grant writing feasibility and success.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874005","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