{"title":"Immunogenomic cancer evolution: A framework to understand cancer immunosuppression","authors":"Shogo Kumagai, Yusaku Momoi, Hiroyoshi Nishikawa","doi":"10.1126/sciimmunol.abo5570","DOIUrl":"https://doi.org/10.1126/sciimmunol.abo5570","url":null,"abstract":"The process of tumor development involves tumor cells eluding detection and suppression of immune responses, which can cause decreased tumor cell antigenicity, expression of immunosuppressive molecules, and immunosuppressive cell recruitment to the tumor microenvironment (TME). Immunologically and genomically integrated analysis (immunogenomic analysis) of patient specimens has revealed that oncogenic aberrant signaling is involved in both carcinogenesis and immune evasion. In noninflamed cancers such as <jats:italic>epidermal growth factor receptor</jats:italic> ( <jats:italic>EGFR</jats:italic> )–mutated lung cancers, genetic abnormalities in cancer cells contribute to the formation of an immunosuppressive TME by recruiting immunosuppressive cells, which cannot be fully explained by the cancer immunoediting hypothesis. This review summarizes the latest findings regarding the links between cancer genetic abnormalities and immunosuppression causing clinical resistance to immunotherapy. We propose the concepts of immunogenomic cancer evolution, in which cancer cell genomic evolution shapes the immunosuppressive TME, and immunogenomic precision medicine, in which cancer immunotherapy can be combined with molecularly targeted reagents that modulate the immunosuppressive TME.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"215 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723818","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}
Asma Farhat, Mariem Radhouani, Florian Deckert, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anna Hakobyan, Felicitas Oberndorfer, Jessica Brösamlen, Anastasiya Hladik, Karin Lakovits, Fanzhe Meng, Federica Quattrone, Louis Boon, Cornelia Vesely, Philipp Starkl, Nicole Boucheron, Jörg Menche, Joris van der Veeken, Wilfried Ellmeier, Anna-Dorothea Gorki, Clarissa Campbell, Riem Gawish, Sylvia Knapp
{"title":"An aging bone marrow exacerbates lung fibrosis by fueling profibrotic macrophage persistence","authors":"Asma Farhat, Mariem Radhouani, Florian Deckert, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anna Hakobyan, Felicitas Oberndorfer, Jessica Brösamlen, Anastasiya Hladik, Karin Lakovits, Fanzhe Meng, Federica Quattrone, Louis Boon, Cornelia Vesely, Philipp Starkl, Nicole Boucheron, Jörg Menche, Joris van der Veeken, Wilfried Ellmeier, Anna-Dorothea Gorki, Clarissa Campbell, Riem Gawish, Sylvia Knapp","doi":"10.1126/sciimmunol.adk5041","DOIUrl":"https://doi.org/10.1126/sciimmunol.adk5041","url":null,"abstract":"Pulmonary fibrosis is an incurable disease that manifests with advanced age. Yet, how hematopoietic aging influences immune responses and fibrosis progression remains unclear. Using heterochronic bone marrow transplant mouse models, we found that an aged bone marrow exacerbates lung fibrosis irrespective of lung tissue age. Upon lung injury, there was an increased accumulation of monocyte-derived alveolar macrophages (Mo-AMs) driven by cell-intrinsic hematopoietic aging. These Mo-AMs exhibited an enhanced profibrotic profile and stalled maturation into a homeostatic, tissue-resident phenotype. This delay was shaped by cell-extrinsic environmental signals such as reduced pulmonary interleukin-10 (IL-10), perpetuating a profibrotic macrophage state. We identified regulatory T cells (T <jats:sub>regs</jats:sub> ) as critical providers of IL-10 upon lung injury that promote Mo-AM maturation and attenuate fibrosis progression. Our study highlights the impact of an aging bone marrow on lung immune regulation and identifies T <jats:sub>reg</jats:sub> -mediated IL-10 signaling as a promising target to mitigate fibrosis and promote tissue repair.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"57 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723816","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}
Kathleen A. M. Mills, Frederike Westermann, Vanessa Espinosa, Eric Rosiek, Jigar V. Desai, Mariano A. Aufiero, Yahui Guo, Fitty L. Liu, Kennedy A. Mitchell, Selma Tuzlak, Donatella De Feo, Michail S. Lionakis, Amariliz Rivera, Burkhard Becher, Tobias M. Hohl
{"title":"GM-CSF–mediated epithelial-immune cell cross-talk orchestrates pulmonary immunity to Aspergillus fumigatus","authors":"Kathleen A. M. Mills, Frederike Westermann, Vanessa Espinosa, Eric Rosiek, Jigar V. Desai, Mariano A. Aufiero, Yahui Guo, Fitty L. Liu, Kennedy A. Mitchell, Selma Tuzlak, Donatella De Feo, Michail S. Lionakis, Amariliz Rivera, Burkhard Becher, Tobias M. Hohl","doi":"10.1126/sciimmunol.adr0547","DOIUrl":"10.1126/sciimmunol.adr0547","url":null,"abstract":"<div ><i>Aspergillus fumigatus</i> causes life-threatening mold pneumonia in immunocompromised patients, particularly in those with quantitative or qualitative defects in neutrophils. Whereas innate immune cell cross-talk licenses neutrophil antifungal activity in the lung, the role of epithelial cells in this process is unknown. Here, we find that surfactant protein C (SPC)–expressing lung epithelial cells integrate infection-induced interleukin-1 and type III interferon signaling to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) preferentially at local sites of fungal infection and neutrophil influx. Using in vivo models that distinguish the role of GM-CSF during acute infection from its homeostatic function in alveolar macrophage survival and surfactant catabolism, we demonstrate that epithelial-derived GM-CSF increases the accumulation and fungicidal activity of GM-CSF–responsive neutrophils, which is essential for host survival. Our findings establish SPC<sup>+</sup> epithelial cells as a central player in regulating the quality and strength of neutrophil-dependent immunity against inhaled mold pathogens.</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":"https://www.science.org/doi/reader/10.1126/sciimmunol.adr0547","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666292","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}
Yao Li, Jiongliang Wang, Linfu Zhou, Wenbin Gu, Le Qin, Dongdong Peng, Shanglin Li, Diwei Zheng, Qiting Wu, Youguo Long, Yao Yao, Shouheng Lin, Mingwei Sun, Xiaofei Zhang, Jie Wang, Pentao Liu, Xiangqian Kong, Peng Li
{"title":"DNMT1 inhibition reprograms T cells to NK-like cells with potent antitumor activity","authors":"Yao Li, Jiongliang Wang, Linfu Zhou, Wenbin Gu, Le Qin, Dongdong Peng, Shanglin Li, Diwei Zheng, Qiting Wu, Youguo Long, Yao Yao, Shouheng Lin, Mingwei Sun, Xiaofei Zhang, Jie Wang, Pentao Liu, Xiangqian Kong, Peng Li","doi":"10.1126/sciimmunol.adm8251","DOIUrl":"10.1126/sciimmunol.adm8251","url":null,"abstract":"<div >Inactivation of the transcription factor BCL11B reprograms T cells into induced-T-to-NK cells (ITNKs). However, it remains unclear how BCL11B suppresses natural killer (NK) cell transcriptional programs. Here, we identified that the DNA methyltransferase DNMT1 physically interacts with BCL11B, increasing BCL11B stability and the fidelity of DNA methylation maintenance for NK cell–related genes, thereby repressing their expression. Moreover, DNMT1 maintains the epigenetic silencing of a distinct subset of NK cell–related genes independent of BCL11B. DNMT1 inhibition or depletion reprograms T cells and chimeric antigen receptor (CAR)–T cells into NK-like cells that exhibit more robust antitumor effects than BCL11B-deficient ITNKs and parental CAR-T cells. Moreover, H3K27me3 (trimethylation of histone 3 lysine 27) synergizes with DNA methylation to repress NK cell–related pathways, and combined EZH2 (enhancer of zeste homolog 2) and DNMT1 inhibition potentiates both the reprogramming and cytotoxicity of NK-like cells. Our findings uncover the molecular mechanisms that safeguard T cell identity and provide a rationale for deriving NK-like cells with epigenetic inhibitors for cancer immunotherapy.</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":"143665976","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}
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}
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":"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}
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}
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}
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