Science Immunology最新文献_第3页

Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity

IF 24.8 1区医学

Science Immunology Pub Date : 2025-03-07 DOI: 10.1126/sciimmunol.ado1710

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}

引用次数: 0

MBPeace treaty: How myelin self-peptides broker CNS tolerance

IF 17.6 1区医学

Science Immunology Pub Date : 2025-03-07

Isabelle Leo, Etienne Caron

引用次数: 0

Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity

IF 17.6 1区医学

Science Immunology Pub Date : 2025-03-07

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}

引用次数: 0

Dynamic STING repression orchestrates immune cell development and function

IF 24.8 1区医学

Science Immunology Pub Date : 2025-03-07 DOI: 10.1126/sciimmunol.ado9933

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 Sting1 IRES-EGFP reporter and conditional Sting1 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 + 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}

引用次数: 0

Trouble at the border: An invading gut bacterium can break tolerance to self-RNA

IF 17.6 1区医学

Science Immunology Pub Date : 2025-03-07

Rachael A. Clark

引用次数: 0

Dynamic STING repression orchestrates immune cell development and function

IF 17.6 1区医学

Science Immunology Pub Date : 2025-03-07

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":"","DOIUrl":"","url":null,"abstract":"<div >STING is an essential component of the innate immune system, yet homeostatic STING expression patterns and regulation are unknown. Using Sting1IRES-EGFP reporter and conditional Sting1 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+ 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.</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":"143583700","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

Trouble at the border: An invading gut bacterium can break tolerance to self-RNA 边界上的麻烦入侵的肠道细菌能打破对自身 RNA 的耐受性

IF 24.8 1区医学

Science Immunology Pub Date : 2025-03-07 DOI: 10.1126/sciimmunol.adx0218

Rachael A. Clark

引用次数: 0

Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate

IF 17.6 1区医学

Science Immunology Pub Date : 2025-03-07

Yinghui J. Huang, Shin Foong Ngiow, Amy E. Baxter, Sasikanth Manne, Simone L. Park, Jennifer E. Wu, Omar Khan, Josephine R. Giles, E. John Wherry

{"title":"Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate","authors":"Yinghui J. Huang, Shin Foong Ngiow, Amy E. Baxter, Sasikanth Manne, Simone L. Park, Jennifer E. Wu, Omar Khan, Josephine R. Giles, E. John Wherry","doi":"","DOIUrl":"","url":null,"abstract":"<div >Although checkpoint blockade temporarily improves exhausted CD8 T (Tex) cell function, the underlying Tex epigenetic landscape remains largely unchanged, preventing durable Tex “reinvigoration” in cancer and chronic infections. The transcription factor TOX initiates Tex epigenetic programming, yet it remains unclear whether TOX continually preserves Tex biology after Tex establishment. Here, we demonstrated that induced TOX ablation in committed Tex cells resulted in apoptotic-driven loss of Tex cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed Tex cells. Moreover, TOX removal endows established Tex cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established Tex cells acts as a durable epigenetic barrier reinforcing the Tex developmental fate. TOX manipulation even after Tex establishment could therefore provide therapeutic opportunities to rewire Tex cells in chronic infections or cancer.</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":"143583692","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

MBPeace treaty: How myelin self-peptides broker CNS tolerance.

IF 17.6 1区医学

Science Immunology Pub Date : 2025-03-07 DOI: 10.1126/sciimmunol.adx0208

Isabelle Leo, Etienne Caron

引用次数: 0

Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate TOX 的持续表达可保护耗竭的 CD8 T 细胞表观遗传命运

IF 24.8 1区医学

Science Immunology Pub Date : 2025-03-07 DOI: 10.1126/sciimmunol.ado3032

Yinghui J. Huang, Shin Foong Ngiow, Amy E. Baxter, Sasikanth Manne, Simone L. Park, Jennifer E. Wu, Omar Khan, Josephine R. Giles, E. John Wherry

{"title":"Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate","authors":"Yinghui J. Huang, Shin Foong Ngiow, Amy E. Baxter, Sasikanth Manne, Simone L. Park, Jennifer E. Wu, Omar Khan, Josephine R. Giles, E. John Wherry","doi":"10.1126/sciimmunol.ado3032","DOIUrl":"https://doi.org/10.1126/sciimmunol.ado3032","url":null,"abstract":"Although checkpoint blockade temporarily improves exhausted CD8 T (T ex ) cell function, the underlying T ex epigenetic landscape remains largely unchanged, preventing durable T ex “reinvigoration” in cancer and chronic infections. The transcription factor TOX initiates T ex epigenetic programming, yet it remains unclear whether TOX continually preserves T ex biology after T ex establishment. Here, we demonstrated that induced TOX ablation in committed T ex cells resulted in apoptotic-driven loss of T ex cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed T ex cells. Moreover, TOX removal endows established T ex cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established T ex cells acts as a durable epigenetic barrier reinforcing the T ex developmental fate. TOX manipulation even after T ex establishment could therefore provide therapeutic opportunities to rewire T ex cells in chronic infections or cancer.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"30 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575440","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