JCI insight最新文献

Unique T cell signatures associated with reduced Chlamydia trachomatis reinfection in a highly exposed cohort.

IF 6.3 1区医学

JCI insight Pub Date : 2025-02-27 DOI: 10.1172/jci.insight.189388

Kacy S Yount, Chi-Jane Chen, Avinash Kollipara, Chuwen Liu, Neha Vivek Mokashi, Xiaojing Zheng, C Bruce Bagwell, Taylor B Poston, Harold C Wiesenfeld, Sharon L Hillier, Catherine M O'Connell, Natalie Stanley, Toni Darville

{"title":"Unique T cell signatures associated with reduced Chlamydia trachomatis reinfection in a highly exposed cohort.","authors":"Kacy S Yount, Chi-Jane Chen, Avinash Kollipara, Chuwen Liu, Neha Vivek Mokashi, Xiaojing Zheng, C Bruce Bagwell, Taylor B Poston, Harold C Wiesenfeld, Sharon L Hillier, Catherine M O'Connell, Natalie Stanley, Toni Darville","doi":"10.1172/jci.insight.189388","DOIUrl":"10.1172/jci.insight.189388","url":null,"abstract":"Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection globally. Understanding natural immunity to CT will inform vaccine design. This study aimed to profile immune cells and associated functional features in CT-infected women, and determine immune profiles associated with reduced risk of ascended endometrial CT infection and CT reinfection. PBMCs from CT-exposed women were profiled by mass cytometry and random forest models identified key features that distinguish outcomes. CT+ participants exhibited higher frequencies of CD4+ Th2, Th17, and Th17 DN CD4 T effector memory (TEM) cells than uninfected participants with decreased expression of T cell activation and differentiation markers. Minimal differences were detected between women with or without endometrial CT infection. Participants who remained follow-up negative (FU-) showed higher frequencies of CD4 T central memory (TCM) Th1, Th17, Th1/17, and Th17 DN but reduced CD4 TEM Th2 cells than FU+ participants. Expression of markers associated with central memory and Th17 lineage were increased on T cell subsets among FU- participants. These data indicate that peripheral T cells exhibit distinct features associated with resistance to CT reinfection. The highly plastic Th17 lineage appears to contribute to protection. Addressing these immune nuances could promote efficacy of CT vaccines.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523345","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

Sequential JAK inhibition enhances anti-tumor immunity after combined anti-PD-1 and anti-CTLA4.

IF 6.3 1区医学

JCI insight Pub Date : 2025-02-27 DOI: 10.1172/jci.insight.187921

Marcel Arias-Badia, PeiXi Chen, Yee May Lwin, Aahir Srinath, Aram Lyu, Zenghua Fan, Serena S Kwek, Diamond N Luong, Ali Setayesh, Mason Sakamoto, Matthew Clark, Averey Lea, Rachel M Wolters, Andrew Goodearl, Fiona A Harding, Jacob V Gorman, Wendy Ritacco, Lawrence Fong

{"title":"Sequential JAK inhibition enhances anti-tumor immunity after combined anti-PD-1 and anti-CTLA4.","authors":"Marcel Arias-Badia, PeiXi Chen, Yee May Lwin, Aahir Srinath, Aram Lyu, Zenghua Fan, Serena S Kwek, Diamond N Luong, Ali Setayesh, Mason Sakamoto, Matthew Clark, Averey Lea, Rachel M Wolters, Andrew Goodearl, Fiona A Harding, Jacob V Gorman, Wendy Ritacco, Lawrence Fong","doi":"10.1172/jci.insight.187921","DOIUrl":"https://doi.org/10.1172/jci.insight.187921","url":null,"abstract":"While immune checkpoint inhibition (CPI) has reshaped cancer treatment, the majority of cancer patients do not benefit from this approach, which can also cause immune-related adverse events. Induction of IFNγ responses is thought be necessary for anti-tumor immunity, but growing evidence also implicates IFNγ as a tumor-intrinsic mediator of CPI resistance. CPI-induced IFNγ mediates activation-induced cell death in T cells as an immune-intrinsic mechanism of resistance. In this study, we show that transient block of IFNγ signaling through administration of the JAK1 inhibitor ABT-317 enhances anti-tumor T cell responses with CPI in pre-clinical models. Importantly, sequential but not concomitant ABT-317 treatment led to significantly reduced toxicity and improved tumor efficacy. Sequential treatment reduced activation-induced T cell death and enhanced expansion of tumor-reactive T cell subsets with increased effector function in vivo and ex vivo. Only CPI in combination with ABT-317 also enhanced memory responses by protecting mice from tumor rechallenge. These results demonstrate that JAK inhibition within a discrete time window following CPI addresses an immune-intrinsic mechanism of therapeutic resistance.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523337","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

The XCL1/XCR1 axis is upregulated in type 1 diabetes and aggravates its pathogenesis.

IF 6.3 1区医学

JCI insight Pub Date : 2025-02-27 DOI: 10.1172/jci.insight.178743

Camilla Tondello, Christine Bender, Gregory J Golden, Deborah Puppe, Elisa Blickberndt, Monika Bayer, Giulia K Buchmann, Josef Pfeilschifter, Malte Bachmann, Edith Hintermann, Ralf P Brandes, Michael R Betts, Richard A Kroczek, Urs Christen

{"title":"The XCL1/XCR1 axis is upregulated in type 1 diabetes and aggravates its pathogenesis.","authors":"Camilla Tondello, Christine Bender, Gregory J Golden, Deborah Puppe, Elisa Blickberndt, Monika Bayer, Giulia K Buchmann, Josef Pfeilschifter, Malte Bachmann, Edith Hintermann, Ralf P Brandes, Michael R Betts, Richard A Kroczek, Urs Christen","doi":"10.1172/jci.insight.178743","DOIUrl":"https://doi.org/10.1172/jci.insight.178743","url":null,"abstract":"Type 1 diabetes (T1D) is precipitated by the autoimmune destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans. Chemokines have been identified as major conductors of islet infiltration by autoaggressive leukocytes, including antigen-presenting cells and islet autoantigen-specific T cells. We have previously generated a roadmap of gene expression in the islet microenvironment during T1D in a mouse model and found that most of the chemokine axes are chronically upregulated during T1D. The XCL1/XCR1 chemokine axis is of particular interest, since XCR1 is exclusively expressed on conventional dendritic cells type 1 (cDC1) that excel by their high capacity for T cell activation. Here we demonstrate cDC1 expressing XCR1 are present in and around the islets of patients with T1D and of islet-autoantibody positive individuals. Further, we show that XCL1 plays an important role in the attraction of highly potent dendritic cells expressing XCR1 to the islets in an inducible mouse model for T1D. XCL1-deficient mice display a diminished infiltration of XCR1+ cDC1 and subsequently a reduced magnitude and activity of islet autoantigen-specific T cells resulting in a profound decrease in T1D incidence. Interference with the XCL1/XCR1 chemokine axis might constitute a novel therapy for T1D.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523341","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

The transcription factor ZNF469 regulates collagen production in liver fibrosis.

IF 6.3 1区医学

JCI insight Pub Date : 2025-02-25 DOI: 10.1172/jci.insight.182232

Sebastian Steinhauser, David Estoppey, Dennis P Buehler, Yanhua Xiong, Nicolas Pizzato, Amandine Rietsch, Fabian Wu, Nelly Leroy, Tiffany Wunderlin, Isabelle Claerr, Philipp Tropberger, Miriam Müller, Alexandra Vissieres, Lindsay M Davison, Eric H Farber-Eger, Quinn S Wells, Quanhu Sheng, Sebastian Bergling, Sophia A Wild, Pierre Moulin, Jiancong Liang, Wayne J English, Brandon Williams, Judith Knehr, Marc Altorfer, Alejandro Reyes, Johannes Voshol, Craig Mickanin, Dominic Hoepfner, Florian Nigsch, Mathias Frederiksen, Charles R Flynn, Barna D Fodor, Jonathan D Brown, Christian Kolter

{"title":"The transcription factor ZNF469 regulates collagen production in liver fibrosis.","authors":"Sebastian Steinhauser, David Estoppey, Dennis P Buehler, Yanhua Xiong, Nicolas Pizzato, Amandine Rietsch, Fabian Wu, Nelly Leroy, Tiffany Wunderlin, Isabelle Claerr, Philipp Tropberger, Miriam Müller, Alexandra Vissieres, Lindsay M Davison, Eric H Farber-Eger, Quinn S Wells, Quanhu Sheng, Sebastian Bergling, Sophia A Wild, Pierre Moulin, Jiancong Liang, Wayne J English, Brandon Williams, Judith Knehr, Marc Altorfer, Alejandro Reyes, Johannes Voshol, Craig Mickanin, Dominic Hoepfner, Florian Nigsch, Mathias Frederiksen, Charles R Flynn, Barna D Fodor, Jonathan D Brown, Christian Kolter","doi":"10.1172/jci.insight.182232","DOIUrl":"https://doi.org/10.1172/jci.insight.182232","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD)-characterized by excess accumulation of fat in the liver-now affects one third of the world's population. As MASLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply characterized cohort of patients spanning the full histopathologic spectrum of MASLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of MASLD-associated liver fibrosis.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501376","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

Transcriptomic responses of lung mesenchymal cells during pneumonia.

IF 6.3 1区医学

JCI insight Pub Date : 2025-02-25 DOI: 10.1172/jci.insight.177084

Alicia M Soucy, Jourdan E Brune, Archana Jayaraman, Anukul T Shenoy, Filiz T Korkmaz, Neelou S Etesami, Bradley E Hiller, Ian Mc Martin, Wesley N Goltry, Catherine T Ha, Nicholas A Crossland, Joshua D Campbell, Thomas G Beach, Katrina E Traber, Matthew R Jones, Lee J Quinton, Markus Bosmann, Charles W Frevert, Joseph P Mizgerd

{"title":"Transcriptomic responses of lung mesenchymal cells during pneumonia.","authors":"Alicia M Soucy, Jourdan E Brune, Archana Jayaraman, Anukul T Shenoy, Filiz T Korkmaz, Neelou S Etesami, Bradley E Hiller, Ian Mc Martin, Wesley N Goltry, Catherine T Ha, Nicholas A Crossland, Joshua D Campbell, Thomas G Beach, Katrina E Traber, Matthew R Jones, Lee J Quinton, Markus Bosmann, Charles W Frevert, Joseph P Mizgerd","doi":"10.1172/jci.insight.177084","DOIUrl":"https://doi.org/10.1172/jci.insight.177084","url":null,"abstract":"The role of mesenchymal cells during respiratory infection is not well defined, including whether, which, and how the different types of mesenchymal cells respond. We collected all mesenchymal cells from lung single-cell suspensions of mice that were naïve (after receiving only saline vehicle), pneumonic (after intratracheal instillation of pneumococcus 24 hours previously), or resolved from infection (after non-lethal pneumococcal infections 6 weeks previously) and performed single-cell RNA sequencing. Cells clustered into five well-separated groups based on their transcriptomes: matrix fibroblasts, myofibroblasts, pericytes, smooth muscle cells, and mesothelial cells. Fibroblasts were the most abundant and could be further segregated into Pdgfra+Npnt+Ces1d+Col13a1+ alveolar fibroblasts and Cd9+Pi16+Sca1+Col14a1+ adventitial fibroblasts. The cells from naïve and resolved groups overlapped in dimension reduction plots, suggesting the mesenchymal cells returned to baseline transcriptomes after resolution. During pneumonia, all mesenchymal cells responded with altered transcriptomes, revealing a core response that had been conserved across cell types as well as distinct mesenchymal cell type-specific responses. The different subsets of fibroblasts induced similar gene sets, but the alveolar fibroblasts responded more strongly than the adventitial fibroblasts. These data demonstrated diverse and specialized immune activities of lung mesenchymal cells during pneumonia.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501378","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

Atypical memory B cells acquire Breg phenotypes in hepatocellular carcinoma.

IF 6.3 1区医学

JCI insight Pub Date : 2025-02-25 DOI: 10.1172/jci.insight.187025

Shi Yong Neo, Timothy Wai Ho Shuen, Shruti Khare, Joni Chong, Maichan Lau, Niranjan Shirgaonkar, Levene Chua, Junzhe Zhao, Keene Lee, Charmaine Tan, Rebecca Ba, Janice Lim, Joelle Chua, Hui Shi Cheong, Hui Min Chai, Chung Yip Chan, Alexander Yaw Fui Chung, Peng Chung Cheow, Prema Raj Jeyaraj, Jin Yao Teo, Ye Xin Koh, Aik Yong Chok, Pierce Kah Hoe Chow, Brian Goh, Wei Keat Wan, Wei Qiang Leow, Tracy Jie Zhen Loh, Po Yin Tang, Jayanthi Karunanithi, Nye Thane Ngo, Tony Kiat Hon Lim, Shengli Xu, Ramanuj Dasgupta, Han Chong Toh, Kong-Peng Lam

{"title":"Atypical memory B cells acquire Breg phenotypes in hepatocellular carcinoma.","authors":"Shi Yong Neo, Timothy Wai Ho Shuen, Shruti Khare, Joni Chong, Maichan Lau, Niranjan Shirgaonkar, Levene Chua, Junzhe Zhao, Keene Lee, Charmaine Tan, Rebecca Ba, Janice Lim, Joelle Chua, Hui Shi Cheong, Hui Min Chai, Chung Yip Chan, Alexander Yaw Fui Chung, Peng Chung Cheow, Prema Raj Jeyaraj, Jin Yao Teo, Ye Xin Koh, Aik Yong Chok, Pierce Kah Hoe Chow, Brian Goh, Wei Keat Wan, Wei Qiang Leow, Tracy Jie Zhen Loh, Po Yin Tang, Jayanthi Karunanithi, Nye Thane Ngo, Tony Kiat Hon Lim, Shengli Xu, Ramanuj Dasgupta, Han Chong Toh, Kong-Peng Lam","doi":"10.1172/jci.insight.187025","DOIUrl":"https://doi.org/10.1172/jci.insight.187025","url":null,"abstract":"The functional plasticity of tumor-infiltrating B (TIL-B) cells spans from anti-tumor responses to non-canonical immune suppression. Yet, how tumor microenvironment (TME) influences TIL-B development is still underappreciated. Our current study integrated single cell transcriptomics and BCR (B cell receptor) sequencing to profile TIL-B phenotypes and clonalities in hepatocellular carcinoma (HCC). Using trajectory and gene regulatory network analysis, we were able to characterize plasma cells, memory and naïve B cells within the HCC TME and further revealed a downregulation of BCR-signaling genes in plasma cells and a subset of inflammatory TNF+ memory B cells. Within the TME, non-switch memory B cell subset acquires an age-associated B cell phenotype (TBET+, CD11c+) and expressed higher levels of PD-L1, CD25 and granzyme B. We further demonstrated that the presence of HCC tumor cells could confer suppressive functions on peripheral blood B cells which in turn, dampen T cell co-stimulation. To the best of our knowledge, these findings represent novel mechanisms of non-canonical immune suppression in HCC. While previous studies identified atypical memory B cells in chronic hepatitis and across several solid cancer types, we further highlighted their potential role as regulatory B cells (Bregs) within both the TME and peripheral blood of HCC patients.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501374","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

Adiponectin signaling regulates urinary bladder function by blunting smooth muscle purinergic contractility.

IF 6.3 1区医学

JCI insight Pub Date : 2025-02-24 DOI: 10.1172/jci.insight.188780

Zhaobo Luo, Ali Wu, Simon Robson, Seth L Alper, Weiqun Yu

{"title":"Adiponectin signaling regulates urinary bladder function by blunting smooth muscle purinergic contractility.","authors":"Zhaobo Luo, Ali Wu, Simon Robson, Seth L Alper, Weiqun Yu","doi":"10.1172/jci.insight.188780","DOIUrl":"https://doi.org/10.1172/jci.insight.188780","url":null,"abstract":"Lower urinary tract symptoms (LUTS) affect approximately 50% of the population over 40 years of age and are strongly associated with obesity and metabolic syndrome. Adipose tissue plays a key role in obesity/metabolic syndrome by releasing adipokines that regulate systemic energy/lipid metabolism, insulin resistance, and inflammation. Adiponectin (ADPN), the most abundant adipokine, modulates energy/metabolism homeostasis through its insulin-sensitizing and antiinflammatory effects. Human plasma ADPN levels are inversely associated with obesity and diabetes. To the best of our knowledge, the role of adipokines such as ADPN in the LUTS associated with obesity/metabolic syndrome remains unknown. We have tested such a possible role in a global ADPN-knockout (Adpn-/-) mouse model. Adpn-/- mice exhibited increased voiding frequency, small voids, and reduced bladder smooth muscle (BSM) contractility, with absence of purinergic contraction. Molecular examination indicated significantly altered metabolic and purinergic pathways. The ADPN receptor agonist AdipoRon was found to abolish acute BSM contraction. Intriguingly, both AMPK activators and inhibitors also abolished BSM purinergic contraction. These data indicate the important contribution of what we believe is a novel ADPN signaling pathway to the regulation of BSM contractility. Dysregulation of this ADPN signaling pathway might be an important mechanism leading to LUTS associated with obesity/metabolic syndrome.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 4","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483167","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

CD4+ T cell-innate immune crosstalk is critical during Staphylococcus aureus craniotomy infection.

IF 6.3 1区医学

JCI insight Pub Date : 2025-02-24 DOI: 10.1172/jci.insight.183327

Gunjan Kak, Zachary Van Roy, Rachel W Fallet, Lee E Korshoj, Tammy Kielian

{"title":"CD4+ T cell-innate immune crosstalk is critical during Staphylococcus aureus craniotomy infection.","authors":"Gunjan Kak, Zachary Van Roy, Rachel W Fallet, Lee E Korshoj, Tammy Kielian","doi":"10.1172/jci.insight.183327","DOIUrl":"https://doi.org/10.1172/jci.insight.183327","url":null,"abstract":"Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. Staphylococcus aureus accounts for half of craniotomy infections, increasing morbidity in a medically fragile patient population. T cells preferentially traffic to the brain during craniotomy infection; however, their functional importance is unknown. Using a mouse model of S. aureus craniotomy infection, CD4+ T cells were critical for bacterial containment, as treatment of WT animals with anti-CD4 exacerbated infection that was similar to phenotypes in Rag1-/- mice. Single-cell RNA-Seq (scRNA-Seq) revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent that displayed Th1- and Th17-like characteristics, and adoptive transfer of either subset in Rag1-/- animals during early infection prevented S. aureus outgrowth. scRNA-Seq identified a robust IFN signature in several innate immune clusters, and examination of cell-to-cell interactions revealed extensive T cell crosstalk with monocytes/macrophages that was also observed in human craniotomy infection. A cooperative role for Th1 and Th17 responses was demonstrated by treatment of Ifng-/- mice with IL-17A neutralizing antibody that recapitulated phenotypes in Rag1-/- animals. Collectively, these findings implicate Th1- and Th17-mediated proinflammatory responses in shaping the innate immune landscape for S. aureus containment during craniotomy infection.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 4","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483181","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

NKG2D blockade impairs tissue-resident memory T cell accumulation and reduces chronic lung allograft dysfunction.

IF 6.3 1区医学

JCI insight Pub Date : 2025-02-24 DOI: 10.1172/jci.insight.184048

Kaveh Moghbeli, Madeline A Lipp, Marta Bueno, Andrew Craig, Michelle Rojas, Minahal Abbas, Zachary I Lakkis, Byron Chuan, John Sembrat, Kentaro Noda, Daniel J Kass, Kong Chen, Li Fan, Tim Oury, Zihe Zhou, Xingan Wang, John F McDyer, Oliver Eickelberg, Mark E Snyder

{"title":"NKG2D blockade impairs tissue-resident memory T cell accumulation and reduces chronic lung allograft dysfunction.","authors":"Kaveh Moghbeli, Madeline A Lipp, Marta Bueno, Andrew Craig, Michelle Rojas, Minahal Abbas, Zachary I Lakkis, Byron Chuan, John Sembrat, Kentaro Noda, Daniel J Kass, Kong Chen, Li Fan, Tim Oury, Zihe Zhou, Xingan Wang, John F McDyer, Oliver Eickelberg, Mark E Snyder","doi":"10.1172/jci.insight.184048","DOIUrl":"https://doi.org/10.1172/jci.insight.184048","url":null,"abstract":"Chronic lung allograft dysfunction (CLAD) substantially limits long-term survival following lung transplantation. To identify potential targets for CLAD prevention, T cells from explanted CLAD lungs and lung-draining lymph nodes, as well as diseased and nondiseased controls were isolated and single-cell RNA sequencing and TCR sequencing were performed. TCR sequencing revealed a clonally expanded population of CD8+ tissue-resident memory T cells (TRMs) with high cytotoxic potential, including upregulation of KLRK1, encoding the co-receptor NKG2D. These cytotoxic CD8+ TRMs accumulated around the CLAD airways and had a 100-fold increase in clonal overlap with lung-draining lymph nodes when compared with non-CLAD lungs. Using a murine model of orthotopic lung transplantation, we confirmed that cytotoxic CD8+ TRM accumulation was due to chronic rejection and not transplantation alone. Furthermore, blocking NKG2D in vivo attenuated the airway remodeling following transplantation and diminished airway accumulation of CD8+ T cells. Our findings support NKG2D as a potential therapeutic target for CLAD, affecting cytotoxic CD8+ TRM accumulation.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 4","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483234","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

C-terminal FGF-23 production coupling with aldosterone via FAM20C and predicting cardiovascular events in primary aldosteronism.

IF 6.3 1区医学

JCI insight Pub Date : 2025-02-24 DOI: 10.1172/jci.insight.166461

Vin-Cent Wu, Kang-Yung Peng, Tsu-I Chen, Chiao-Yin Sun, Hung-Wei Liao, Chieh-Kai Chan, Yen-Hung Lin, Hung-Hsiang Liou, Jeff S Chueh

{"title":"C-terminal FGF-23 production coupling with aldosterone via FAM20C and predicting cardiovascular events in primary aldosteronism.","authors":"Vin-Cent Wu, Kang-Yung Peng, Tsu-I Chen, Chiao-Yin Sun, Hung-Wei Liao, Chieh-Kai Chan, Yen-Hung Lin, Hung-Hsiang Liou, Jeff S Chueh","doi":"10.1172/jci.insight.166461","DOIUrl":"https://doi.org/10.1172/jci.insight.166461","url":null,"abstract":"This study examined the involvement of fibroblast growth factor-23 (FGF-23) in primary aldosteronism (PA), a condition characterized by elevated aldosterone levels and hypertension. We recruited patients with unilateral PA (uPA) and observed increased levels of C-terminal FGF-23 (cFGF-23) and C-terminal to intact FGF-23 (iFGF-23) in patients with uPA compared with essential hypertension control participants. Elevated preoperative cFGF-23 levels were associated with adverse outcomes, including mortality and cardiovascular or kidney events. Plasma cFGF-23 levels demonstrated a nonlinear rise with aldosterone, but iFGF-23 levels were not correlated with plasma aldosterone concentration. Higher cFGF-23 levels independently predicted hypertension remission after adrenalectomy for patients with uPA. Patients with uPA, who exhibited elevated cFGF-23 levels, had decreased levels after adrenalectomy. In cell cultures, aldosterone enhanced cleavage of iFGF-23, leading to increased levels of cFGF-23 fragments, an effect mitigated by silencing of family with sequence similarity 20, member C (FAM20C). However, the enhancement of cFGF-23 levels remained unaffected by the furin inhibitor. The study suggests that aldosterone influences FGF-23 phosphorylation by interacting with FAM20C, with docking experiments indicating aldosterone's binding to FAM20C. This work highlights that patients with uPA with elevated cFGF-23 levels are associated with cardiovascular risks, and adrenalectomy reduces cFGF-23. Aldosterone likely promotes cFGF-23 production through FAM20C-mediated phosphorylation of iFGF-23.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 4","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483185","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