The Journal of Clinical Investigation最新文献_第3页

HIF-1 promotes murine breast cancer brain metastasis by increasing production of integrin β3-containing extracellular vesicles. HIF-1通过增加含有整合素β3的细胞外囊泡的产生促进小鼠乳腺癌脑转移。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci190470

Yongkang Yang,Chelsey Chen,Yajing Lyu,Olesia Gololobova,Xin Guo,Tina Yi-Ting Huang,Vijay Ramu,Varen Talwar,Elizabeth E Wicks,Shaima Salman,Daiana Drehmer,Dominic Dordai,Qiaozhu Zuo,Kenneth W Witwer,Kathleen L Gabrielson,Gregg L Semenza

{"title":"HIF-1 promotes murine breast cancer brain metastasis by increasing production of integrin β3-containing extracellular vesicles.","authors":"Yongkang Yang,Chelsey Chen,Yajing Lyu,Olesia Gololobova,Xin Guo,Tina Yi-Ting Huang,Vijay Ramu,Varen Talwar,Elizabeth E Wicks,Shaima Salman,Daiana Drehmer,Dominic Dordai,Qiaozhu Zuo,Kenneth W Witwer,Kathleen L Gabrielson,Gregg L Semenza","doi":"10.1172/jci190470","DOIUrl":"https://doi.org/10.1172/jci190470","url":null,"abstract":"Brain metastasis is a major cause of breast cancer (BC) mortality, but the cellular and molecular mechanisms have not been fully elucidated. BC cells must breach the blood-brain barrier in order to colonize the brain. Here, we determined that integrin β3 (ITGB3) expression mediated by hypoxia-inducible factor 1 (HIF-1) plays a critical role in metastasis of BC cells to the brain. Hypoxia stimulated BC cell migration and invasion ex vivo and brain colonization in vivo. Knockdown of either HIF-1α or ITGB3 expression impaired brain colonization by human or mouse BC cells injected into the cardiac left ventricle. Exposure of BC cells to hypoxia increased expression of ITGB3 and its incorporation into small extracellular vesicles (EVs). EVs harvested from the conditioned medium of hypoxic BC cells showed increased retention in the brain after intracardiac injection that was HIF-1α and ITGB3 dependent. EVs from hypoxic BC cells showed binding to brain endothelial cells (ECs), leading to increased EC-BC cell interaction, increased vascular endothelial growth factor receptor 2 signaling, increased EC permeability, and increased transendothelial migration of BC cells. Taken together, our studies implicate HIF-1-stimulated production of ITGB3+ EVs as a key mechanism by which hypoxia promotes BC brain metastasis.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

What's on the menu?: metabolic constraints in the pancreatic tumor microenvironment. 菜单上有什么？胰腺肿瘤微环境中的代谢限制。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci191940

Colin Sheehan,Alexander Muir

{"title":"What's on the menu?: metabolic constraints in the pancreatic tumor microenvironment.","authors":"Colin Sheehan,Alexander Muir","doi":"10.1172/jci191940","DOIUrl":"https://doi.org/10.1172/jci191940","url":null,"abstract":"The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is composed of a dense stromal compartment and is poorly vascularized, resulting in limited nutrient delivery. As a result, PDAC cells must adapt to cope with the metabolic stresses brought on by TME nutrient limitation. In this article, we first review recent studies that have provided quantitative measurements of nutrient levels in the PDAC TME. These studies have provided a new understanding of the nutrient limitations and metabolic stresses that occur in PDAC. We next discuss the adaptive strategies employed by PDAC in response to TME nutrient limitation. We propose that PDAC adaptations to metabolic stress can be generalized into four categories: (a) cutting down on metabolic costs by recycling metabolites and suppressing nonessential processes, (b) upregulating biosynthetic pathways to meet TME metabolic demands, (c) supporting essential metabolic processes with alternative fuel sources, and (d) dampening antiproliferative and cell death responses that nutrient limitation normally triggers. Improving our understanding of the nutrient limitations within the TME, and the adaptations cells employ to cope with these stresses, provides a more complete picture of PDAC biology and reveals new opportunities for therapeutic targeting of this disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"109 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Early neoplastic lesions of the pancreas: initiation, progression, and opportunities for precancer interception. 胰腺早期肿瘤病变：起始、进展和癌前阻断的机会。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci191937

Brian A Pedro,Laura D Wood

引用次数: 0

The GLYT1 inhibitor bitopertin mitigates erythroid PPIX production and liver disease in erythroid protoporphyria. GLYT1抑制剂bitopertin减轻红细胞PPIX的产生和红细胞原卟啉症的肝脏疾病。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci181875

Sarah Ducamp,Min Wu,Juan Putra,Dean R Campagna,Yi Xiang,Vu Hong,Matthew M Heeney,Amy K Dickey,Rebecca K Leaf,Mark D Fleming,Brian MacDonald,Paul J Schmidt

{"title":"The GLYT1 inhibitor bitopertin mitigates erythroid PPIX production and liver disease in erythroid protoporphyria.","authors":"Sarah Ducamp,Min Wu,Juan Putra,Dean R Campagna,Yi Xiang,Vu Hong,Matthew M Heeney,Amy K Dickey,Rebecca K Leaf,Mark D Fleming,Brian MacDonald,Paul J Schmidt","doi":"10.1172/jci181875","DOIUrl":"https://doi.org/10.1172/jci181875","url":null,"abstract":"Erythropoietic protoporphyria (EPP) is a genetic disorder typically resulting from decreased ferrochelatase (FECH) activity, the last enzyme in heme biosynthesis. Patients with X-linked protoporphyria (XLPP) have an overlapping phenotype caused by increased activity of 5-aminolevulinic acid synthase 2 (ALAS2), the first enzyme in erythroid heme synthesis. In both cases, protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in plasma and tissues. Patients develop acute phototoxicity reactions upon brief exposure to sunlight. Some also suffer from chronic liver disease, and a small fraction develop acute cholestatic liver failure. Therapeutic options are limited, and none, save hematopoietic stem cell transplantation, directly targets erythroid PPIX accumulation. Bitopertin is an investigational orally available small molecule inhibitor of the erythroid cell surface glycine transporter GLYT1. We establish the bitopertin PPIX inhibitory half-maximal effective concentration in a human erythroblast EPP model and confirm a marked reduction of PPIX in erythroblasts derived from EPP patients. We demonstrate that bitopertin also reduces erythrocyte and plasma PPIX accumulation in vivo in mouse models of both EPP and XLPP. Finally, the reduction in erythroid PPIX ameliorates liver disease in the EPP mouse model. Altogether, these data support the development of bitopertin to treat patients with EPP or XLPP.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NFAT5 dictates crosstalk between intestinal epithelial regenerative capacity and microbiota in murine colitis models. 在小鼠结肠炎模型中，NFAT5决定肠上皮再生能力和微生物群之间的串扰。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci183093

Se Hyeon Park,Dae Hee Cheon,Yu-Mi Kim,Yeji Choi,Yong-Joon Cho,Bong-Ki Hong,Sang-Hyun Cho,Mi-Na Kweon,Hyug Moo Kwon,Eugene B Chang,Donghyun Kim,Wan-Uk Kim

{"title":"NFAT5 dictates crosstalk between intestinal epithelial regenerative capacity and microbiota in murine colitis models.","authors":"Se Hyeon Park,Dae Hee Cheon,Yu-Mi Kim,Yeji Choi,Yong-Joon Cho,Bong-Ki Hong,Sang-Hyun Cho,Mi-Na Kweon,Hyug Moo Kwon,Eugene B Chang,Donghyun Kim,Wan-Uk Kim","doi":"10.1172/jci183093","DOIUrl":"https://doi.org/10.1172/jci183093","url":null,"abstract":"Hypertonic and hyperosmolar stimuli frequently pose challenges to the intestinal tract. Therefore, a resilient epithelial barrier is essential for maintaining gut homeostasis in the presence of osmotic perturbations. NFAT5, an osmosensitive transcription factor, primarily maintains cellular homeostasis under hypertonic conditions. However, the osmoprotective role of NFAT5 in enterocyte homeostasis is poorly understood. Here, we demonstrate that NFAT5 is critical for the survival and proliferation of intestinal epithelial cells (IECs) and that its deficiency accelerates chemically induced or spontaneous colitis in mice. Mechanistically, NFAT5 promotes the survival of IECs and the renewal of intestinal stem cells, thereby regulating the production of mucus and antimicrobial compounds, including RegIII and lysozyme, which consequently shape the gut microbial composition to prevent colitis. Transcriptome analysis identifies HSP70 as a key downstream target of NFAT5 in epithelial regeneration. Loss- and gain-of-function experiments of HSP70 revealed that NFAT5 mitigates experimental colitis through IEC Hsp70, which protected stem cells from inflammation-induced injury and maintained barrier function. In conclusion, our study demonstrates a previously unknown role for NFAT5 in dictating the crosstalk between intestinal stem cells and the microbiota, underscoring the importance of the NFAT5-HSP70 axis in maintaining epithelial regeneration related to gut barrier function, balancing microbial composition, and subsequently preventing colitis progression.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"109 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evolving concepts in adjuvant/neoadjuvant therapy for resectable pancreas cancer. 可切除胰腺癌辅助/新辅助治疗概念的演变。

The Journal of Clinical Investigation Pub Date : 2025-07-15 DOI: 10.1172/jci191944

John M Bryant,Luis Ruffolo,Kevin Soares,Sarah Hoffe,Andrew M Lowy

引用次数: 0

Gut-specific histamine 3 receptor signaling orchestrates microglia-dependent resolution of peripheral inflammation. 肠道特异性组胺3受体信号调控小胶质细胞依赖性外周炎症的消退。

The Journal of Clinical Investigation Pub Date : 2025-07-10 DOI: 10.1172/jci184697

Kerstin Dürholz,Leona Ehnes,Mathias Linnerbauer,Eva Schmid,Heike Danzer,Michael Hinzpeter-Schmidt,Lena Lößlein,Lena Amend,Michael Frech,Vugar Azizov,Fabian Schälter,Arne Gessner,Sébastien Lucas,Till-Robin Lesker,R Verena Taudte,Jörg Hofmann,Felix Beyer,Hadar Bootz-Maoz,Yasmin Reich,Hadar Romano,Daniele Mauro,Ruth Beckervordersandforth,Maja Skov Kragsnaes,Torkell Ellingsen,Wei Xiang,Aiden Haghikia,Cezmi A Akdis,Francesco Ciccia,Tobias Bäuerle,Kerstin Sarter,Till Strowig,Nissan Yissachar,Georg Schett,Veit Rothhammer,Mario M Zaiss

{"title":"Gut-specific histamine 3 receptor signaling orchestrates microglia-dependent resolution of peripheral inflammation.","authors":"Kerstin Dürholz,Leona Ehnes,Mathias Linnerbauer,Eva Schmid,Heike Danzer,Michael Hinzpeter-Schmidt,Lena Lößlein,Lena Amend,Michael Frech,Vugar Azizov,Fabian Schälter,Arne Gessner,Sébastien Lucas,Till-Robin Lesker,R Verena Taudte,Jörg Hofmann,Felix Beyer,Hadar Bootz-Maoz,Yasmin Reich,Hadar Romano,Daniele Mauro,Ruth Beckervordersandforth,Maja Skov Kragsnaes,Torkell Ellingsen,Wei Xiang,Aiden Haghikia,Cezmi A Akdis,Francesco Ciccia,Tobias Bäuerle,Kerstin Sarter,Till Strowig,Nissan Yissachar,Georg Schett,Veit Rothhammer,Mario M Zaiss","doi":"10.1172/jci184697","DOIUrl":"https://doi.org/10.1172/jci184697","url":null,"abstract":"Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (CNS) activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such factor. We show that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord and restore homeostatic microglia, thereby reducing inflammation in the joints. Selective histamine 3 receptor (H3R) signaling in the intestine is critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the short-chain fatty acid (SCFA) propionate identified one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut-CNS-joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"694 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combinatorial therapy regimens targeting preclinical models of melanoma resistant to immune checkpoint blockade. 针对抗免疫检查点阻断的黑色素瘤临床前模型的联合治疗方案。

The Journal of Clinical Investigation Pub Date : 2025-07-10 DOI: 10.1172/jci185220

Imran Khan,Aida Rodriguez-Brotons,Anukana Bhattacharjee,Vladimir Bezrookove,Altaf Dar,David De Semir,Mehdi Nosrati,Ryan Ice,Liliana Soroceanu,Stanley P Leong,Kevin B Kim,Yihui Shi,James E Cleaver,James R Miller,Pierre-Yves Desprez,John M Kirkwood,Marcus Bosenberg,Nathan Salomonis,Sean McAllister,Mohammed Kashani-Sabet

{"title":"Combinatorial therapy regimens targeting preclinical models of melanoma resistant to immune checkpoint blockade.","authors":"Imran Khan,Aida Rodriguez-Brotons,Anukana Bhattacharjee,Vladimir Bezrookove,Altaf Dar,David De Semir,Mehdi Nosrati,Ryan Ice,Liliana Soroceanu,Stanley P Leong,Kevin B Kim,Yihui Shi,James E Cleaver,James R Miller,Pierre-Yves Desprez,John M Kirkwood,Marcus Bosenberg,Nathan Salomonis,Sean McAllister,Mohammed Kashani-Sabet","doi":"10.1172/jci185220","DOIUrl":"https://doi.org/10.1172/jci185220","url":null,"abstract":"Few effective therapeutic options exist following progression on immune checkpoint blockade (ICB) for melanoma. Here we utilize a platform incorporating transcriptomic profiling, high-throughput drug screening (HTDS) and murine models to demonstrate the pre-clinical efficacy of several combinatorial regimens against ICB-resistant melanoma. Transcriptomic analysis of ICB-resistant melanomas demonstrated activation of several targetable pathways. HTDS targeting these pathways identified several effective combinations in ICB-resistant patient-derived xenograft models. The combination of cobimetinib and regorafenib (termed Cobi+Reg) emerged as a particularly promising regimen, with efficacy against distinct molecular melanoma subtypes and following progression on ICB in immunocompetent models. Transcriptomic and spatial analysis of Cobi+Reg-treated tumors demonstrated upregulation of antigen presentation machinery, with concomitantly increased activated T cell infiltration. Combining Cobi+Reg with ICB was superior to either modality in vivo. This analytical platform exploits the biology of ICB-resistant melanoma to identify therapeutic vulnerabilities, resulting in the identification of drug combinations that form the basis for rational clinical trial design in the setting of advanced melanoma resistant to ICB.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion. TBX3的体细胞突变通过加速VLDL分泌促进肝脏克隆扩增。

The Journal of Clinical Investigation Pub Date : 2025-07-10 DOI: 10.1172/jci191855

Gregory Mannino,Gabriella Quinn,Min Zhu,Zixi Wang,Xun Wang,Boyuan Li,Meng-Hsiung Hsieh,Thomas Mathews,Lauren Zacharias,Wen Gu,Purva Gopal,Natalia Brzozowska,Peter Campbell,Matt Hoare,Glen Liszczak,Hao Zhu

{"title":"Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion.","authors":"Gregory Mannino,Gabriella Quinn,Min Zhu,Zixi Wang,Xun Wang,Boyuan Li,Meng-Hsiung Hsieh,Thomas Mathews,Lauren Zacharias,Wen Gu,Purva Gopal,Natalia Brzozowska,Peter Campbell,Matt Hoare,Glen Liszczak,Hao Zhu","doi":"10.1172/jci191855","DOIUrl":"https://doi.org/10.1172/jci191855","url":null,"abstract":"Somatic mutations that increase clone fitness or resist disease are positively selected, but the impact of these mutations on organismal health remains unclear. We previously showed that Tbx3 deletion increases hepatocyte fitness within fatty livers. Here, we detected TBX3 somatic mutations in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). In mice, Tbx3 deletion protected against, whereas Tbx3 overexpression exacerbated MASLD. Tbx3 deletion reduced lipid overload by accelerating VLDL secretion. Choline deficient diets, which block VLDL secretion, abrogated this protective effect. TBX3 transcriptionally suppressed the conventional secretory pathway and cholesterol biosynthesis. Hdlbp is a direct target of TBX3 that is responsible for the altered VLDL secretion. In contrast to wild-type TBX3, the TBX3 I155S and A280S mutations found in patients failed to suppress VLDL secretion. In conclusion, TBX3 mutant clones expand during MASLD through increased lipid disposal, demonstrating that clonal fitness can benefit the liver at the cost of hyperlipidemia.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"109 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Treg activation during allograft tolerance induction requires mitochondrial-induced TGFβ1 in type 1 conventional dendritic cells. 同种异体移植物耐受诱导过程中的Treg激活需要线粒体诱导的1型常规树突状细胞中的TGFβ1。

The Journal of Clinical Investigation Pub Date : 2025-07-10 DOI: 10.1172/jci178960

Samantha L Schroth,Lei Zhang,Rebecca Tl Jones,Kristofor Glinton,Nikita L Mani,Hiroyasu Inui,Jesse T Davidson,Samuel E Weinberg,Navdeep Chandel,Maria-Luisa Alegre,Edward B Thorp

{"title":"Treg activation during allograft tolerance induction requires mitochondrial-induced TGFβ1 in type 1 conventional dendritic cells.","authors":"Samantha L Schroth,Lei Zhang,Rebecca Tl Jones,Kristofor Glinton,Nikita L Mani,Hiroyasu Inui,Jesse T Davidson,Samuel E Weinberg,Navdeep Chandel,Maria-Luisa Alegre,Edward B Thorp","doi":"10.1172/jci178960","DOIUrl":"https://doi.org/10.1172/jci178960","url":null,"abstract":"The role of type 1 conventional dendritic cells (cDC1) in tolerance induction to solid organ allografts is unknown and important for strategies that seek to prolong allograft viability. Using a murine model deficient in cDC1s, we report cDC1s are required for donor antigen and costimulation blockade (DST + CoB) tolerance induction and survival of cardiac allografts. cDC1 deficiency led to decreases in CD4+CD25+FoxP3+ T cells within both allograft and spleen tissue of transplant recipients and this was found to be antigen specific. Donor antigen stimulation induced TGF-β1 expression both in vivo cDC1 and in vitro Flt3L derived cDC1. Genetic deletion of Tgfβ1 in cDC1s prevented induction of antigen specific CD4+CD25+FoxP3+ T cells and was associated with cardiac allograft rejection. In parallel, single-cell RNA sequencing and metabolic analysis revealed upregulation of cDC1 mitochondrial metabolic signatures after in vivo exposure to DST + CoB. Genetic inactivation of cDC1 mitochondrial metabolism reduced expression of cDC1 TGF-β1, decreased antigen specific T regulatory cell populations, and impaired allograft tolerance. Taken together, our findings newly implicate cDC1s in strategies to preserve solid organ allografts and also implicate mitochondrial metabolism of cDC1s as a molecular mechanism to enhance the generation of antigen-specific CD4+CD25+FoxP3+ T cells through TGF-β1.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0