Francis Baumgartner, Stefanos A. Bamopoulos, Laura Faletti, Hsiang-Jung Hsiao, Maximilian Holz, Irene Gonzalez-Menendez, Llorenç Boldo, Arik Horne, Sanket Gosavi, Ceren Özerdem, Nikita Singh, Sven Liebig, Senthilkumar Ramamoorthy, Malte Lehmann, Uta Demel, Anja A. Kühl, Tim Wartewig, Jürgen Ruland, Frank T. Wunderlich, Markus Schick, Wolfgang Walther, Stefan Rose-John, Simon Haas, Leticia Quintanilla-Martinez, Stefan Feske, Stephan Ehl, Rainer Glauben, Ulrich Keller
{"title":"Activation of gp130 signaling in T cells drives TH17-mediated multi-organ autoimmunity","authors":"Francis Baumgartner, Stefanos A. Bamopoulos, Laura Faletti, Hsiang-Jung Hsiao, Maximilian Holz, Irene Gonzalez-Menendez, Llorenç Boldo, Arik Horne, Sanket Gosavi, Ceren Özerdem, Nikita Singh, Sven Liebig, Senthilkumar Ramamoorthy, Malte Lehmann, Uta Demel, Anja A. Kühl, Tim Wartewig, Jürgen Ruland, Frank T. Wunderlich, Markus Schick, Wolfgang Walther, Stefan Rose-John, Simon Haas, Leticia Quintanilla-Martinez, Stefan Feske, Stephan Ehl, Rainer Glauben, Ulrich Keller","doi":"10.1126/scisignal.adc9662","DOIUrl":null,"url":null,"abstract":"<div >The IL-6–gp130–STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3<sup>GOF</sup>) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, <i>L-gp130</i>, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3<sup>GOF</sup> disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (T<sub>H</sub>17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4<sup>+</sup> and CD8<sup>+</sup> T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3<sup>GOF</sup> mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to T<sub>H</sub>17-driven autoimmunity that phenotypically resembles human STAT3<sup>GOF</sup> disease.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Signaling","FirstCategoryId":"99","ListUrlMain":"https://www.science.org/doi/10.1126/scisignal.adc9662","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The IL-6–gp130–STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3GOF) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, L-gp130, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3GOF disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (TH17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4+ and CD8+ T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3GOF mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to TH17-driven autoimmunity that phenotypically resembles human STAT3GOF disease.
期刊介绍:
"Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets.
The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment.
In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.