JCI insightPub Date : 2025-03-04DOI: 10.1172/jci.insight.184128
Olivia Bonduelle, Tristan Delory, Isabelle Franco Moscardini, Marion Ghidi, Selma Bennacer, Michele Wokam, Mathieu Lenormand, Melissa Petrier, Olivier Rogeaux, Simon de Bernard, Karine Alves, Julien Nourikyan, Bruno Lina, Behazine Combadiere, Cécile Janssen
{"title":"Boosting effect of high-dose influenza vaccination on innate immunity among elderly: a randomized-control trial.","authors":"Olivia Bonduelle, Tristan Delory, Isabelle Franco Moscardini, Marion Ghidi, Selma Bennacer, Michele Wokam, Mathieu Lenormand, Melissa Petrier, Olivier Rogeaux, Simon de Bernard, Karine Alves, Julien Nourikyan, Bruno Lina, Behazine Combadiere, Cécile Janssen","doi":"10.1172/jci.insight.184128","DOIUrl":"https://doi.org/10.1172/jci.insight.184128","url":null,"abstract":"<p><strong>Background: </strong>The high-dose quadrivalent influenza vaccine (QIV-HD) showed superior efficacy against laboratory-confirmed illness than the standard-dose quadrivalent influenza vaccine (QIV-SD) in randomized-controlled trials with elderly. However, specific underlying mechanism remains unclear.</p><p><strong>Methods: </strong>This Phase-IV randomized control trial compared early innate responses induced by QIV-HD and QIV-SD in 59 subjects aged >65 years. Systemic innate cells and gene signatures at Day (D) 0 and D1, hemagglutinin inhibition antibody (HIA) titers at D0 and D21 post-vaccination were assessed.</p><p><strong>Results: </strong>QIV-HD elicited robust humoral response with significantly higher antibody titers and seroconversion rates than QIV-SD. At D1 post-vaccination, QIV-HD recipients showed significant reduction in innate cells, including conventional dendritic cells and natural killer cells than QIV-SD, correlating with significantly increased HIA titers at D21. Blood transcriptomic analysis revealed greater amplitude of gene expression in QIV-HD arm, encompassing genes related to innate immune response, interferons, and antigen processing and presentation and correlated with humoral responses. Interestingly, comparative analysis with a literature dataset from young adults vaccinated with influenza standard-dose vaccine highlighted strong similarities in gene expression patterns and biological pathways with the elderly vaccinated with QIV-HD.</p><p><strong>Conclusion: </strong>QIV-HD induces higher HIA titers than QIV-SD, a youthful boost of the innate gene expression significantly associated with high HIA titers.</p><p><strong>Trial registration: </strong>EudraCT Number: 2021-004573-32.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556968","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}
JCI insightPub Date : 2025-03-04DOI: 10.1172/jci.insight.184493
Lawrence F Brass, Maurizio Tomaiuolo, Aislinn Wallace, Myles H Akabas
{"title":"Admissions to MD-PhD programs: how well do application metrics predict short- or long-term physician-scientist outcomes?","authors":"Lawrence F Brass, Maurizio Tomaiuolo, Aislinn Wallace, Myles H Akabas","doi":"10.1172/jci.insight.184493","DOIUrl":"10.1172/jci.insight.184493","url":null,"abstract":"<p><p>MD-PhD programs prepare physicians for research-focused careers. The challenge for admissions committees is to select from among their applicants those who will achieve this goal, becoming leaders in academic medicine and biomedical research. Although holistic practices are encouraged, the temptation remains to use metrics such as grade point average, Medical College Admission Test scores, and postbaccalaureate gap length, combined with race and ethnicity, age at college graduation, and sex to select whom to interview and admit. Here, we asked whether any of these metrics predict performance in training or career paths after graduation. Data were drawn from the National MD-PhD Program Outcomes Study with information on 4,659 alumni and 593 MD-PhD graduates of the Albert Einstein College of Medicine and the University of Pennsylvania. The Penn-Einstein dataset included admissions committee summative scores, attrition, and the number and impact of PhD publications. Output metrics included time to degree, eventual employment in workplaces consistent with MD-PhD training goals, and self-reported research effort. Data were analyzed using machine learning and multivariate linear regression. The results show that none of the applicant metrics, individually or collectively, predicted in-program performance, future research effort, or eventual workplace choices even when comparisons were limited to those in the top and bottom quintiles.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556967","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}
JCI insightPub Date : 2025-03-04DOI: 10.1172/jci.insight.187271
Cody S Nelson, Manuel A Podestà, Maya G Gempler, Jeong-Mi Lee, Cole J Batty, Peterson G Mathenge, Asra Sainju, Matthew R Chang, Hanzhong Ke, Pragya Chandrakar, Elsa Bechu, Sierra Richardson, Cecilia B Cavazzoni, Stefan G Tullius, Reza Abdi, Musie Ghebremichael, Marcia C Haigis, Wayne A Marasco, Peter T Sage
{"title":"The inflammaging microenvironment induces dysfunctional rewiring of Tfh cell differentiation.","authors":"Cody S Nelson, Manuel A Podestà, Maya G Gempler, Jeong-Mi Lee, Cole J Batty, Peterson G Mathenge, Asra Sainju, Matthew R Chang, Hanzhong Ke, Pragya Chandrakar, Elsa Bechu, Sierra Richardson, Cecilia B Cavazzoni, Stefan G Tullius, Reza Abdi, Musie Ghebremichael, Marcia C Haigis, Wayne A Marasco, Peter T Sage","doi":"10.1172/jci.insight.187271","DOIUrl":"https://doi.org/10.1172/jci.insight.187271","url":null,"abstract":"<p><p>Humoral immunity is orchestrated by follicular helper T (Tfh) cells, which promote cognate B cells to produce high-affinity, protective antibodies. In aged individuals, humoral immunity after vaccination is diminished despite the presence of Tfh cells, suggesting defects after initial Tfh formation. In this study, we utilized both murine and human systems to investigate how aging alters Tfh cell differentiation after influenza vaccination. We found that young Tfh cells underwent progressive differentiation after influenza vaccination, culminating in clonal expansion of effector-like cells in both draining lymph nodes and blood. In aging, early stages of Tfh development occurred normally. However, aging rewired the later stages of development in Tfh cells, resulting in a transcriptional program reflective of cellular senescence, sustained pro-inflammatory cytokine production, and metabolic reprogramming. We investigated the extent to which this rewiring of aged Tfh cells is due to the age-associated inflammatory (\"inflammaging\") microenvironment and found that this setting was sufficient to both block the transition of Tfh cells to a post-effector resting state and to skew Tfh cells towards the age-rewired state. Together, these data suggest that aging dampens humoral immunity by cytokine-mediated rewiring of late effector Tfh cell differentiation into an activated, yet less functional, cellular state.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556842","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}
JCI insightPub Date : 2025-03-04DOI: 10.1172/jci.insight.180809
Yi Sun, Wai-Kit Tam, Manyu Zhu, Qiuji Lu, Mengqi Yu, Yuching Hsu, Peng Chen, Peng Zhang, Minmin Lyu, Yongcan Huang, Zhaomin Zheng, Xintao Zhang, Victor Y Leung
{"title":"MMP12-dependent myofibroblast formation contributes to nucleus pulposus fibrosis.","authors":"Yi Sun, Wai-Kit Tam, Manyu Zhu, Qiuji Lu, Mengqi Yu, Yuching Hsu, Peng Chen, Peng Zhang, Minmin Lyu, Yongcan Huang, Zhaomin Zheng, Xintao Zhang, Victor Y Leung","doi":"10.1172/jci.insight.180809","DOIUrl":"10.1172/jci.insight.180809","url":null,"abstract":"<p><p>Intervertebral disc degeneration (IDD) is associated with low back pain, a leading cause of disability worldwide. Fibrosis of nucleus pulposus (NP) is a principal component of IDD, featuring an accumulation of myofibroblast-like cells. Previous study indicates that matrix metalloproteinase 12 (MMP12) expression is upregulated in IDD, but its role remains largely unexplored. We here showed that TGF-β1 could promote myofibroblast-like differentiation of human NP cells along with an induction of MMP12 expression. Intriguingly, MMP12 knockdown not only ameliorated the myofibroblastic phenotype but also increased chondrogenic marker expression. Transcriptome analysis revealed that the MMP12-mediated acquisition of myofibroblast phenotype was coupled to processes related to fibroblast activation and osteogenesis and to pathways mediated by MAPK and Wnt signaling. Injury induced mouse IDD showed NP fibrosis with marked increase of collagen deposition and αSMA-expressing cells. In contrast, MMP12-KO mice exhibited largely reduced collagen I and III but increased collagen II and aggrecan deposition, indicating an inhibition of NP fibrosis along with an enhanced cartilaginous matrix remodeling. Consistently, an increase of SOX9+ and CNMD+ but decrease of αSMA+ NP cells was found in the KO. Altogether, our findings suggest a pivotal role of MMP12 in myofibroblast generation, thereby regulating NP fibrosis in IDD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556833","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}
JCI insightPub Date : 2025-03-04DOI: 10.1172/jci.insight.179928
Jessica Day, Cynthia Louis, Kristy Swiderski, Angus Stock, Huon Wong, Wentao Yao, Bonnia Liu, Suba Nadesapillai, Gordon S Lynch, Ian P Wicks
{"title":"Periarticular myositis and muscle fibrosis are cytokine-dependent complications of inflammatory arthritis.","authors":"Jessica Day, Cynthia Louis, Kristy Swiderski, Angus Stock, Huon Wong, Wentao Yao, Bonnia Liu, Suba Nadesapillai, Gordon S Lynch, Ian P Wicks","doi":"10.1172/jci.insight.179928","DOIUrl":"10.1172/jci.insight.179928","url":null,"abstract":"<p><p>The deleterious consequences of chronic synovitis on cartilage, tendon, and bone in rheumatoid arthritis (RA) are well described. In contrast, its effects on periarticular skeletal muscle are under-studied. Furthermore, while TNF inhibition is an effective therapy for RA synovitis, it exacerbates fibrosis in muscle injury models. We aimed to investigate whether myositis and muscle fibrosis are features of inflammatory arthritis and evaluate whether targeted RA therapies influence these disease features. Periarticular muscle was analyzed in murine models of poly- and monoarticular inflammatory arthritis: serum transfer-induced arthritis, collagen-induced arthritis, K/BxN, and antigen-induced arthritis (AIA). Periarticular myositis and an increase in muscle fibroadipocyte progenitors (FAPs) were observed in all models, despite diverse arthritogenic mechanisms. Periarticular muscle fibrosis was observed from day 15 in AIA. Neither etanercept nor baricitinib suppressed periarticular myositis or subsequent fibrosis compared to vehicle, despite reducing arthritis. Notably, etanercept failed to prevent muscle fibrosis even when initiated early, but this was not linked to increased FAP survival or collagen production. Corroborating these data, radiographic and histological analyses revealed periarticular myositis in patients with RA. We conclude that periarticular myositis and fibrosis are under-recognized features of inflammatory arthritis. Targeted RA therapies may not prevent periarticular muscle sequelae, despite controlling arthritis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556837","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}
{"title":"Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves antitumor immunity.","authors":"Yanying Yang, Xiaoyan Li, Fangming Liu, Mingyue Ma, Ying Yang, Chengchao Ruan, Yan Lu, Xiaoyang Li, Xiangdong Wang, Yinghong Shi, Zheng Zhang, Hua Wang, Zhouli Cheng, Duojiao Wu","doi":"10.1172/jci.insight.174600","DOIUrl":"10.1172/jci.insight.174600","url":null,"abstract":"<p><p>This study aimed to explore the potential correlation between the metabolic intermediate L-2-hydroxyglutarate (L-2-HG) and T cell exhaustion, as well as the underlying mechanisms involved. In this study, we investigated the presence of exhausted T (Tex) cells in patients under certain conditions: HIV infection, chronic leukemia, and hepatocellular carcinoma. To gain insights into the epigenetic signatures and transcriptome changes in Tex cells, we employed a combination of RNA-seq and ATAC-seq analyses. To evaluate the impact of L-2-HG on mitochondrial function, differentiation, and antitumor capacity of Tex cells, we utilized in vitro cell culture experiments and animal tumor models. We observed mitochondrial depolarization and metabolic dysfunction in Tex cells, accompanied by a significant reduction in L-2-HG levels. Moreover, altered epigenetic characteristics were observed in Tex cells, including a substantial increase in H3K27me3 abundance. Culturing Tex cells with L-2-HG demonstrated improved mitochondrial metabolism, reduced H3K27me3 abundance, and enhanced memory T cell differentiation. In a mouse melanoma tumor model, L-2-HG-treated CD8+ T cells for adoptive therapy led to significantly reduced tumor volume and significantly enhanced effector function of T cells. The study revealed that L-2-HG acted as an immune metabolite through epigenetic modifications of Tex cells.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567118","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}
JCI insightPub Date : 2025-03-04DOI: 10.1172/jci.insight.190105
Marco Galvan, Mina Fujitani, Samuel R Heaselgrave, Shreya Thomas, Bandy Chen, Jenny J Lee, Steven C Wyler, Joel K Elmquist, Teppei Fujikawa
{"title":"Development and characterization of an Sf-1-Flp mouse model.","authors":"Marco Galvan, Mina Fujitani, Samuel R Heaselgrave, Shreya Thomas, Bandy Chen, Jenny J Lee, Steven C Wyler, Joel K Elmquist, Teppei Fujikawa","doi":"10.1172/jci.insight.190105","DOIUrl":"10.1172/jci.insight.190105","url":null,"abstract":"<p><p>The use of genetically engineered tools, including combinations of Cre-LoxP and Flp-FRT systems, enable the interrogation of complex biology. Steroidogenic factor-1 (SF-1) is expressed in the ventromedial hypothalamic nucleus (VMH). Development of genetic tools, such as mice expressing Flp recombinase (Flp) in SF-1 neurons (Sf-1-Flp), will be useful for future studies that unravel the complex physiology regulated by the VMH. Here, we developed and characterized Sf-1-Flp mice and demonstrated its utility. Flp sequence was inserted into Sf-1 locus with P2A. This insertion did not affect Sf-1 mRNA expression levels and Sf-1-Flp mice do not have any visible phenotypes. They are fertile and metabolically comparable to wild-type littermate mice. Optogenetic stimulation using adeno-associated virus (AAV)-bearing Flp-dependent channelrhodopsin-2 (ChR2) increased blood glucose and skeletal muscle PGC-1α in Sf-1-Flp mice. This was similar to SF-1 neuronal activation using Sf-1-BAC-Cre and AAV-bearing Cre-dependent ChR2. Finally, we generated Sf-1-Flp mice that lack β2-adrenergic receptors (Adrβ2) only in skeletal muscle with a combination of Cre/LoxP technology (Sf-1-Flp::SKM∆Adrβ2). Optogenetic stimulation of SF-1 neurons failed to increase skeletal muscle PGC-1α in Sf-1-Flp::SKM∆Adrβ2 mice, suggesting that Adrβ2 in skeletal muscle is required for augmented skeletal muscle PGC-1α by SF-1 neuronal activation. Our data demonstrate that Sf-1-Flp mice are useful for interrogating complex physiology.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557026","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}
JCI insightPub Date : 2025-02-27DOI: 10.1172/jci.insight.189388
Kacy S Yount, Chi-Jane Chen, Avinash Kollipara, Chuwen Liu, Neha V Mokashi, Xiaojing Zheng, C Bruce Bagwell, Taylor B Poston, Harold C Wiesenfeld, Sharon L Hillier, Catherine M O'Connell, Natalie Stanley, Toni Darville
{"title":"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 V 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":"<p><p>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 distinguished outcomes. CT+ participants exhibited higher frequencies of CD4+ Th2, Th17, and Th17 double-negative (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 was 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.</p>","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}
JCI insightPub Date : 2025-02-27DOI: 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 antitumor 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":"10.1172/jci.insight.187921","url":null,"abstract":"<p><p>While immune checkpoint inhibition (CPI) has reshaped cancer treatment, the majority of patients with cancer do not benefit from this approach, which can also cause immune-related adverse events. Induction of IFN-γ responses is thought be necessary for antitumor immunity, but growing evidence also implicates IFN-γ as a tumor-intrinsic mediator of CPI resistance. CPI-induced IFN-γ mediates activation-induced cell death in T cells as an immune-intrinsic mechanism of resistance. In this study, we found that transient block of IFN-γ signaling through administration of the JAK1 inhibitor ABT-317 enhanced antitumor T cell responses with CPI in preclinical 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.</p>","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}
JCI insightPub Date : 2025-02-27DOI: 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":"10.1172/jci.insight.178743","url":null,"abstract":"<p><p>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 road map 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 DCs type 1 (cDC1) that excel by their high capacity for T cell activation. Here, we demonstrate that cDC1-expressing XCR1 are present in and around the islets of patients with T1D and of individuals with islet autoantibody positivity. Furthermore, we show that XCL1 plays an important role in the attraction of highly potent DCs 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.</p>","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}
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