Weili Xu, Natasha B. Golovchenko, Irving U. Martínez-Vargas, Andrew Fong, Prateeksha Rout, Sajan Achi, Edie B. Bucar, Jonathan J. Hsieh, Kaylynn J. Vidmar, Lanjing Zhang, Alexandros D. Polydorides, Immo Prinz, George Kollias, Mark R. Frey, Theresa T. Pizarro, Michael P. Verzi, Karen L. Edelblum
{"title":"Dysregulation of γδ intraepithelial lymphocytes precedes Crohn’s disease–like ileitis","authors":"Weili Xu, Natasha B. Golovchenko, Irving U. Martínez-Vargas, Andrew Fong, Prateeksha Rout, Sajan Achi, Edie B. Bucar, Jonathan J. Hsieh, Kaylynn J. Vidmar, Lanjing Zhang, Alexandros D. Polydorides, Immo Prinz, George Kollias, Mark R. Frey, Theresa T. Pizarro, Michael P. Verzi, Karen L. Edelblum","doi":"10.1126/sciimmunol.adk7429","DOIUrl":"10.1126/sciimmunol.adk7429","url":null,"abstract":"<div >Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) provide immunosurveillance of the intestinal barrier but are reduced in patients with active Crohn’s disease (CD). Here, we report an underappreciated role for γδ IELs in maintaining immunological tolerance during the onset and progression of CD-like ileitis using TNF<sup>ΔARE/+</sup> mice. We found that TNF-induced down-regulation of epithelial hepatocyte nuclear factor 4-gamma/butyrophilin is followed by a loss of ileal Vγ7 IELs and impaired barrier surveillance before the histological onset of disease. A reduction of immunoregulatory CD39<sup>+</sup> γδ IELs coincided with the influx of immature, peripheral CD39<sup>neg</sup> γδ T cells into the epithelium, leading to an expansion of induced IELs, whereas an earlier depletion of γδ IELs correlated with accelerated onset of ileal inflammation. Our findings identify multiple layers of γδ IEL dysregulation before ileitis development, indicating that the loss of steady-state immunoregulatory γδ IELs may contribute to the initiation of ileal CD.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666294","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}
Nicole M. Carter, Wihib D. Hankore, Yong-Kang Yang, Chao Yang, Shelby M. Hutcherson, Wyatt Fales, Anushka Ghosh, Piyusha Mongia, Sophie Mackinnon, Anna Brennan, Robert D. Leone, Joel L. Pomerantz
{"title":"QRICH1 mediates an intracellular checkpoint for CD8 + T cell activation via the CARD11 signalosome","authors":"Nicole M. Carter, Wihib D. Hankore, Yong-Kang Yang, Chao Yang, Shelby M. Hutcherson, Wyatt Fales, Anushka Ghosh, Piyusha Mongia, Sophie Mackinnon, Anna Brennan, Robert D. Leone, Joel L. Pomerantz","doi":"10.1126/sciimmunol.adn8715","DOIUrl":"https://doi.org/10.1126/sciimmunol.adn8715","url":null,"abstract":"Antigen receptor signaling pathways that control lymphocyte activation depend on signaling hubs and negative regulatory proteins to fine-tune signaling outputs to ensure host defense and avoid pathogenic responses. Caspase recruitment domain–containing protein 11 (CARD11) is a critical signaling scaffold that translates T cell receptor (TCR) triggering into the activation of nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), mechanistic target of rapamycin (mTOR), and Akt. Here, we identify glutamine-rich protein 1 (QRICH1) as a regulator of CARD11 signaling that mediates an intracellular checkpoint for CD8 <jats:sup>+</jats:sup> T cell activation. QRICH1 associates with CARD11 after TCR engagement and negatively regulates CARD11 signaling to NF-κB. QRICH1 binding to CARD11 is controlled by an autoregulatory intramolecular interaction between QRICH1 domains of previously uncharacterized function. QRICH1 controls the antigen-induced activation, proliferation, and effector status of CD8 <jats:sup>+</jats:sup> T cells by regulating numerous genes critical for CD8 <jats:sup>+</jats:sup> T cell function. Our results define a component of antigen receptor signaling circuitry that fine-tunes effector output in response to antigen recognition.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"54 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618477","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}
Ke Wang, Andrea Farrell, Enchen Zhou, Houji Qin, Zixuan Zeng, Kailun Zhou, Karina Cunha e Rocha, Dinghong Zhang, Gaowei Wang, Amha Atakilit, Dean Sheppard, Li-Fan Lu, Chunyu Jin, Wei Ying
{"title":"ATF4 drives regulatory T cell functional specification in homeostasis and obesity","authors":"Ke Wang, Andrea Farrell, Enchen Zhou, Houji Qin, Zixuan Zeng, Kailun Zhou, Karina Cunha e Rocha, Dinghong Zhang, Gaowei Wang, Amha Atakilit, Dean Sheppard, Li-Fan Lu, Chunyu Jin, Wei Ying","doi":"","DOIUrl":"","url":null,"abstract":"<div >Regulatory T cells (T<sub>regs</sub>) have diverse functional specification in homeostasis and disease. However, how liver T<sub>regs</sub> function and are transcriptionally regulated in obesity is not well understood. Here, we identified that effector T<sub>regs</sub> expressing activating transcription factor 4 (ATF4) were enriched in the livers of obese mice. ATF4 was critical for driving an effector T<sub>reg</sub> transcriptional program, and ATF4-expressing T<sub>regs</sub> promoted the development of obesity-induced liver fibrosis by enhancing transforming growth factor–β activation via integrin αvβ8. T<sub>reg</sub>-specific deletion of <i>Atf4</i> resulted in reduced liver T<sub>regs</sub> and attenuation of obesity-induced liver abnormalities. Furthermore, ATF4 was required to promote the differentiation of nonlymphoid tissue T<sub>reg</sub> precursors under steady state. These findings demonstrate that ATF4 is important for regulating T<sub>reg</sub> functional specification in homeostasis and obesity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp7193","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622767","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}
Ke Wang, Andrea Farrell, Enchen Zhou, Houji Qin, Zixuan Zeng, Kailun Zhou, Karina Cunha e Rocha, Dinghong Zhang, Gaowei Wang, Amha Atakilit, Dean Sheppard, Li-Fan Lu, Chunyu Jin, Wei Ying
{"title":"ATF4 drives regulatory T cell functional specification in homeostasis and obesity","authors":"Ke Wang, Andrea Farrell, Enchen Zhou, Houji Qin, Zixuan Zeng, Kailun Zhou, Karina Cunha e Rocha, Dinghong Zhang, Gaowei Wang, Amha Atakilit, Dean Sheppard, Li-Fan Lu, Chunyu Jin, Wei Ying","doi":"10.1126/sciimmunol.adp7193","DOIUrl":"https://doi.org/10.1126/sciimmunol.adp7193","url":null,"abstract":"Regulatory T cells (T <jats:sub>regs</jats:sub> ) have diverse functional specification in homeostasis and disease. However, how liver T <jats:sub>regs</jats:sub> function and are transcriptionally regulated in obesity is not well understood. Here, we identified that effector T <jats:sub>regs</jats:sub> expressing activating transcription factor 4 (ATF4) were enriched in the livers of obese mice. ATF4 was critical for driving an effector T <jats:sub>reg</jats:sub> transcriptional program, and ATF4-expressing T <jats:sub>regs</jats:sub> promoted the development of obesity-induced liver fibrosis by enhancing transforming growth factor–β activation via integrin αvβ8. T <jats:sub>reg</jats:sub> -specific deletion of <jats:italic>Atf4</jats:italic> resulted in reduced liver T <jats:sub>regs</jats:sub> and attenuation of obesity-induced liver abnormalities. Furthermore, ATF4 was required to promote the differentiation of nonlymphoid tissue T <jats:sub>reg</jats:sub> precursors under steady state. These findings demonstrate that ATF4 is important for regulating T <jats:sub>reg</jats:sub> functional specification in homeostasis and obesity.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"5 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618475","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}
Nicole M. Carter, Wihib D. Hankore, Yong-Kang Yang, Chao Yang, Shelby M. Hutcherson, Wyatt Fales, Anushka Ghosh, Piyusha Mongia, Sophie Mackinnon, Anna Brennan, Robert D. Leone, Joel L. Pomerantz
{"title":"QRICH1 mediates an intracellular checkpoint for CD8+ T cell activation via the CARD11 signalosome","authors":"Nicole M. Carter, Wihib D. Hankore, Yong-Kang Yang, Chao Yang, Shelby M. Hutcherson, Wyatt Fales, Anushka Ghosh, Piyusha Mongia, Sophie Mackinnon, Anna Brennan, Robert D. Leone, Joel L. Pomerantz","doi":"","DOIUrl":"","url":null,"abstract":"<div >Antigen receptor signaling pathways that control lymphocyte activation depend on signaling hubs and negative regulatory proteins to fine-tune signaling outputs to ensure host defense and avoid pathogenic responses. Caspase recruitment domain–containing protein 11 (CARD11) is a critical signaling scaffold that translates T cell receptor (TCR) triggering into the activation of nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), mechanistic target of rapamycin (mTOR), and Akt. Here, we identify glutamine-rich protein 1 (QRICH1) as a regulator of CARD11 signaling that mediates an intracellular checkpoint for CD8<sup>+</sup> T cell activation. QRICH1 associates with CARD11 after TCR engagement and negatively regulates CARD11 signaling to NF-κB. QRICH1 binding to CARD11 is controlled by an autoregulatory intramolecular interaction between QRICH1 domains of previously uncharacterized function. QRICH1 controls the antigen-induced activation, proliferation, and effector status of CD8<sup>+</sup> T cells by regulating numerous genes critical for CD8<sup>+</sup> T cell function. Our results define a component of antigen receptor signaling circuitry that fine-tunes effector output in response to antigen recognition.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622800","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":"MBPeace treaty: How myelin self-peptides broker CNS tolerance","authors":"Isabelle Leo, Etienne Caron","doi":"","DOIUrl":"","url":null,"abstract":"<div >Specific MBP-derived self-peptides promote immune tolerance in the CNS and induce an unconventional regulatory T cell response.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583701","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}
Benjamin Klein, Mack B. Reynolds, Bin Xu, Mehrnaz Gharaee-Kermani, Yiqing Gao, Celine C. Berthier, Svenja Henning, Lam C. Tsoi, Shannon N. Loftus, Kelsey E. McNeely, Christine M. Goudsmit, Amanda M. Victory, Craig Dobry, Grace A. Hile, Feiyang Ma, Jessica L. Turnier, Johann E. Gudjonsson, Mary X. O’Riordan, J. Michelle Kahlenberg
{"title":"Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity","authors":"Benjamin Klein, Mack B. Reynolds, Bin Xu, Mehrnaz Gharaee-Kermani, Yiqing Gao, Celine C. Berthier, Svenja Henning, Lam C. Tsoi, Shannon N. Loftus, Kelsey E. McNeely, Christine M. Goudsmit, Amanda M. Victory, Craig Dobry, Grace A. Hile, Feiyang Ma, Jessica L. Turnier, Johann E. Gudjonsson, Mary X. O’Riordan, J. Michelle Kahlenberg","doi":"","DOIUrl":"","url":null,"abstract":"<div >Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. We show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV) B–induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is up-regulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. In patient-derived samples, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB exposure, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS-STING) activation compared with the more conventional B-DNA. ZBP1 knockdown abrogates UVB-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583702","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}
Benjamin Klein, Mack B. Reynolds, Bin Xu, Mehrnaz Gharaee-Kermani, Yiqing Gao, Celine C. Berthier, Svenja Henning, Lam C. Tsoi, Shannon N. Loftus, Kelsey E. McNeely, Christine M. Goudsmit, Amanda M. Victory, Craig Dobry, Grace A. Hile, Feiyang Ma, Jessica L. Turnier, Johann E. Gudjonsson, Mary X. O’Riordan, J. Michelle Kahlenberg
{"title":"Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity","authors":"Benjamin Klein, Mack B. Reynolds, Bin Xu, Mehrnaz Gharaee-Kermani, Yiqing Gao, Celine C. Berthier, Svenja Henning, Lam C. Tsoi, Shannon N. Loftus, Kelsey E. McNeely, Christine M. Goudsmit, Amanda M. Victory, Craig Dobry, Grace A. Hile, Feiyang Ma, Jessica L. Turnier, Johann E. Gudjonsson, Mary X. O’Riordan, J. Michelle Kahlenberg","doi":"10.1126/sciimmunol.ado1710","DOIUrl":"https://doi.org/10.1126/sciimmunol.ado1710","url":null,"abstract":"Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. We show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV) B–induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is up-regulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. In patient-derived samples, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB exposure, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS-STING) activation compared with the more conventional B-DNA. ZBP1 knockdown abrogates UVB-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"18 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575445","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}
Kennady Knox, Devon Jeltema, Nicole Dobbs, Kun Yang, Cong Xing, Kun Song, Zhen Tang, Gustavo Torres-Ramirez, Jiefu Wang, Shan Gao, Tuoqi Wu, Chen Yao, Jian Wang, Nan Yan
{"title":"Dynamic STING repression orchestrates immune cell development and function","authors":"Kennady Knox, Devon Jeltema, Nicole Dobbs, Kun Yang, Cong Xing, Kun Song, Zhen Tang, Gustavo Torres-Ramirez, Jiefu Wang, Shan Gao, Tuoqi Wu, Chen Yao, Jian Wang, Nan Yan","doi":"10.1126/sciimmunol.ado9933","DOIUrl":"https://doi.org/10.1126/sciimmunol.ado9933","url":null,"abstract":"STING is an essential component of the innate immune system, yet homeostatic STING expression patterns and regulation are unknown. Using <jats:italic> Sting1 <jats:sup>IRES-EGFP</jats:sup> </jats:italic> reporter and conditional <jats:italic>Sting1</jats:italic> transgenic mice, we found that regulation of STING expression is critical for immune cell development and functionality. STING expression was repressed in neutrophils, and forced STING expression or signaling drove systemic inflammatory disease. During T lymphocyte development, STING expression was restricted at the double-positive stage via epigenetic silencing by DNA methyltransferase 1. Forced STING expression or signaling impaired T lymphocyte development independent of type I interferon and promoted lineage commitment to innate-like γδ T cells over adaptive αβ T cells. In the tumor microenvironment, CD8 <jats:sup>+</jats:sup> T lymphocytes repressed STING expression, correlating with features of T cell exhaustion in syngeneic mouse tumors and human colorectal cancer. Our data demonstrate the necessity of controlled, rather than ubiquitous, STING expression, uncovering a previously unappreciated dimension of STING pathobiology.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"39 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575442","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":"Trouble at the border: An invading gut bacterium can break tolerance to self-RNA","authors":"Rachael A. Clark","doi":"","DOIUrl":"","url":null,"abstract":"<div >Mouse anti-RNA antibodies triggered by gut <i>E. gallinarum</i> correlate with self-RNA autoantibodies and lupus severity in humans.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583698","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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