Angela R Corrigan, Shin Foong Ngiow, Maura Statzu, Amie Albertus, M Betina Pampena, Jayme M L Nordin, Stephen D Carro, Justin Harper, Rachelle L Stammen, Jennifer Wood, Houping Ni, Justin Su, Marziyeh Hajialyani, Vladimir V Shuvaev, Victor Alcalde, Mohammed-Alkhatim A Ali, Jacob T Hamilton, Rajesvaran Ramalingam, Vincent H Wu, Mirko Paiardini, Drew Weissman, E John Wherry, Edward F Kreider, Michael R Betts
{"title":"In vivo reprogramming of cytotoxic effector CD8 T cells via fractalkine-conjugated mRNA-LNPs.","authors":"Angela R Corrigan, Shin Foong Ngiow, Maura Statzu, Amie Albertus, M Betina Pampena, Jayme M L Nordin, Stephen D Carro, Justin Harper, Rachelle L Stammen, Jennifer Wood, Houping Ni, Justin Su, Marziyeh Hajialyani, Vladimir V Shuvaev, Victor Alcalde, Mohammed-Alkhatim A Ali, Jacob T Hamilton, Rajesvaran Ramalingam, Vincent H Wu, Mirko Paiardini, Drew Weissman, E John Wherry, Edward F Kreider, Michael R Betts","doi":"10.1126/sciimmunol.aec3436","DOIUrl":"10.1126/sciimmunol.aec3436","url":null,"abstract":"<p><p>Selective in vivo reprogramming of cytotoxic effector CD8 T (T<sub>eff</sub>) cells holds tremendous promise as a therapeutic tool but has not yet been accomplished. Here, we demonstrate that fractalkine-conjugated mRNA lipid nanoparticles (mRNA-LNPs) can specifically target and deliver mRNA to CX3CR1<sup>+</sup> T<sub>eff</sub> cells in vitro and in vivo. In mice, fractalkine-conjugated mRNA-LNPs targeted up to 95% of blood and splenic T<sub>eff</sub> cells. In addition, delivery of IL-2-encoding mRNA and human CD62L-encoding mRNA to mouse T<sub>eff</sub> cells enabled robust exogenous IL-2 secretion and CD62L expression. In rhesus macaques, fractalkine-conjugated mRNA-LNPs targeted up to ~100% of peripheral blood T<sub>eff</sub> cells, and delivery of human CD62L-encoding mRNA enabled cell-surface human CD62L expression on peripheral blood T<sub>eff</sub> cells and detection of human CD62L<sup>+</sup> T<sub>eff</sub> cells in lymphoid tissue. Collectively, these data demonstrate the potential of natural receptor ligand-based targeting of mRNA-LNPs for rapid, efficient, and transient in vivo modification of T<sub>eff</sub> cells.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 119","pages":"eaec3436"},"PeriodicalIF":16.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857000","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}
Juan Villar-Vesga, Donatella De Feo, Pauline Clément, Viola Bugada, Elèni Meuffels, Hannah Van Hove, Mitchell Bijnen, James King, Sophie Grundschober, Can Ulutekin, Maria Pena-Francesch, Sara Costa-Pereira, Laura Oberbichler, Violetta Gogoleva, Jeanne Kim, Katarina Wendy Schmidt, Musadiq A Bhat, Deborah Greis, Frauke Seehusen, Francesco Prisco, Urvashi Dalvi, Dietmar Benke, Bettina Schreiner, Tommaso Patriarchi, Florian Ingelfinger, Isabelle C Arnold, Christian Münz, Melanie Greter, Aiman S Saab, Burkhard Becher, Sarah Mundt
{"title":"Monocyte-derived macrophages drive neurological tissue damage through mitochondrial reactive oxygen species.","authors":"Juan Villar-Vesga, Donatella De Feo, Pauline Clément, Viola Bugada, Elèni Meuffels, Hannah Van Hove, Mitchell Bijnen, James King, Sophie Grundschober, Can Ulutekin, Maria Pena-Francesch, Sara Costa-Pereira, Laura Oberbichler, Violetta Gogoleva, Jeanne Kim, Katarina Wendy Schmidt, Musadiq A Bhat, Deborah Greis, Frauke Seehusen, Francesco Prisco, Urvashi Dalvi, Dietmar Benke, Bettina Schreiner, Tommaso Patriarchi, Florian Ingelfinger, Isabelle C Arnold, Christian Münz, Melanie Greter, Aiman S Saab, Burkhard Becher, Sarah Mundt","doi":"10.1126/sciimmunol.adw5197","DOIUrl":"10.1126/sciimmunol.adw5197","url":null,"abstract":"<p><p>Reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs) are widely believed to drive tissue damage in multiple sclerosis (MS), yet the distinct roles of central nervous system (CNS)-resident versus CNS-invading MPs remain unclear. Here, we combined single-cell profiling and conditional gene targeting to map and modulate ROS production across CNS MPs in a preclinical mouse model of MS. We show that monocyte-derived macrophages (MdMs) exhibit a higher oxidative stress gene signature and produce more ROS than microglia (Mglia). Challenging previous assumptions, our findings reveal that phagocytic NADPH oxidase 2 is dispensable for neuroinflammation. In contrast, quenching mitochondrial ROS (mtROS) through mitochondria-targeted catalase (mCAT) expression in MdMs, but not in Mglia, ameliorated disease severity in acute neuroinflammation. Although core phagocyte functions were unaltered in mCAT-expressing MdMs, our results demonstrate a direct neurotoxic role of mtROS. In sum, we identify MdMs as the primary driver of ROS-mediated oxidative neurological tissue damage.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 119","pages":"eadw5197"},"PeriodicalIF":16.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856941","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}
Angela R. Corrigan, Shin Foong Ngiow, Maura Statzu, Amie Albertus, M. Betina Pampena, Jayme M. L. Nordin, Stephen D. Carro, Justin Harper, Rachelle L. Stammen, Jennifer Wood, Houping Ni, Justin Su, Marziyeh Hajialyani, Vladimir V. Shuvaev, Victor Alcalde, Mohammed-Alkhatim A. Ali, Jacob T. Hamilton, Rajesvaran Ramalingam, Vincent H. Wu, Mirko Paiardini, Drew Weissman, E. John Wherry, Edward F. Kreider, Michael R. Betts
{"title":"In vivo reprogramming of cytotoxic effector CD8 T cells via fractalkine-conjugated mRNA-LNPs","authors":"Angela R. Corrigan, Shin Foong Ngiow, Maura Statzu, Amie Albertus, M. Betina Pampena, Jayme M. L. Nordin, Stephen D. Carro, Justin Harper, Rachelle L. Stammen, Jennifer Wood, Houping Ni, Justin Su, Marziyeh Hajialyani, Vladimir V. Shuvaev, Victor Alcalde, Mohammed-Alkhatim A. Ali, Jacob T. Hamilton, Rajesvaran Ramalingam, Vincent H. Wu, Mirko Paiardini, Drew Weissman, E. John Wherry, Edward F. Kreider, Michael R. Betts","doi":"","DOIUrl":"","url":null,"abstract":"<div >Selective in vivo reprogramming of cytotoxic effector CD8 T (T<sub>eff</sub>) cells holds tremendous promise as a therapeutic tool but has not yet been accomplished. Here, we demonstrate that fractalkine-conjugated mRNA lipid nanoparticles (mRNA-LNPs) can specifically target and deliver mRNA to CX3CR1<sup>+</sup> T<sub>eff</sub> cells in vitro and in vivo. In mice, fractalkine-conjugated mRNA-LNPs targeted up to 95% of blood and splenic T<sub>eff</sub> cells. In addition, delivery of IL-2–encoding mRNA and human CD62L-encoding mRNA to mouse T<sub>eff</sub> cells enabled robust exogenous IL-2 secretion and CD62L expression. In rhesus macaques, fractalkine-conjugated mRNA-LNPs targeted up to ~100% of peripheral blood T<sub>eff</sub> cells, and delivery of human CD62L-encoding mRNA enabled cell-surface human CD62L expression on peripheral blood T<sub>eff</sub> cells and detection of human CD62L<sup>+</sup> T<sub>eff</sub> cells in lymphoid tissue. Collectively, these data demonstrate the potential of natural receptor ligand-based targeting of mRNA-LNPs for rapid, efficient, and transient in vivo modification of T<sub>eff</sub> cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 119","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147830231","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":"Erratum for the Research Article \"Single-cell profiling reveals diverse γδ T cell subsets in ulcerative colitis\".","authors":"","doi":"10.1126/sciimmunol.aeh9584","DOIUrl":"10.1126/sciimmunol.aeh9584","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 119","pages":"eaeh9584"},"PeriodicalIF":16.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856931","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":"A parasite partner for regulatory affairs","authors":"Isabella O. Conway, Christopher A. Hunter","doi":"10.1126/sciimmunol.aei2411","DOIUrl":"10.1126/sciimmunol.aei2411","url":null,"abstract":"<div >Targeting Treg cells to mitigate inflammation has been a challenge, but a parasite-derived cytokine may be key to engineering a Treg cell therapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 119","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147820564","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":"B cells gone broad: A deep dive into SARS-CoV-2 antibody breadth","authors":"Easton E. Ford, Melissa L. Smith","doi":"10.1126/sciimmunol.aei2832","DOIUrl":"10.1126/sciimmunol.aei2832","url":null,"abstract":"<div >Antigen-specific B cell profiling uncovers key determinants of SARS-CoV-2 antibody breadth after infection and vaccination.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 119","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147820609","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":"Foxp3 drives context-dependent epigenetic programs that define regulatory T cell molecular identity and function","authors":"Yuxi Wei, Hinako Ago, Ryuichi Murakami, Shotaro Funatsu, Marina Osaki, Akira Nakajima, Yoshinori Hasegawa, Ryoji Kawakami, Shimon Sakaguchi, Shohei Hori","doi":"10.1126/sciimmunol.aed2111","DOIUrl":"10.1126/sciimmunol.aed2111","url":null,"abstract":"<div >Regulatory T cells (T<sub>reg</sub> cells) express the master regulator, Foxp3, and display distinctive epigenetic landscapes ensuring T<sub>reg</sub> cell–specific gene expression and stable suppressive functions, yet Foxp3’s contribution to this epigenetic identity remains unclear. Leveraging Foxp3-transduced conventional T cells as a gain-of-function probe in mice, we identified a previously unrecognized subset that acquires endogenous <i>Foxp3</i> expression, T<sub>reg</sub> cell–like transcriptomic and chromatin features, and suppressive functions exclusively in vivo. These Foxp3-driven features were conserved in T<sub>reg</sub> cells but impaired in Foxp3-mutant T<sub>reg</sub>-like cells, demonstrating a Foxp3 requirement. Induction of endogenous <i>Foxp3</i> expression in vivo required reduced AKT-mTOR signaling and Foxp3-dependent engagement of STAT5 and nuclear factor κB (NF-κB). Temporal chromatin profiling revealed stepwise Foxp3-driven regulatory programs, including a core program shared across T<sub>reg</sub> cell subsets and effector-specific programs, both associated with NF-κB activity and Foxp3 binding. Thus, Foxp3 integrates cell-intrinsic and environmental contexts to drive epigenetic programs defining T<sub>reg</sub> cell identities and functions, with implications for Foxp3-based therapies.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 119","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147820521","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":"Foxp3: The epigenetic engineer of regulatory T cell identity","authors":"Mieke Metzemaekers, Ralph Stadhouders","doi":"10.1126/sciimmunol.aeg4759","DOIUrl":"10.1126/sciimmunol.aeg4759","url":null,"abstract":"<div >Foxp3 exerts context-dependent chromatin-remodeling activity to establish key epigenetic programs that define the functional identity of regulatory T cells (see related Research Article by Wei <i>et al.).</i></div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 119","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147820531","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":"Citraconate preserves T cell stemness and antitumor immunity","authors":"Wenhui Li, Minmin Ge, Ziyi Luo, Minju Ni, Kexin Tang, Chenfeng Han, Jiajia Wang, Yifu Ma, Xiaowei Liu, Kaili Ma, Jingxing Yang, Wenjing Li, Cangang Zhang, Qitai Zhao, Guangcan Shao, Jaeoh Park, Yi Zhang, Yonghong Wan, Baojun Zhang, Gang Wang, Mingjing Shen, Qiang Shan, Feng Guo, Ping-Chih Ho, Liyuan Zhang, Lianjun Zhang","doi":"10.1126/sciimmunol.adz0348","DOIUrl":"10.1126/sciimmunol.adz0348","url":null,"abstract":"<div >Metabolic perturbations in the tumor microenvironment profoundly compromise the stemlike properties and effector functions of CD8 T cells. Deciphering the metabolic circuitry that sustains T cell stemness is critical for reinvigorating tumor-infiltrating lymphocytes and augmenting immunotherapeutic efficacy. Here, we identify citraconate, an itaconate isomer, as a metabolite markedly depleted in CD8 T cells subjected to chronic antigen stimulation or hypoxic conditions. Citraconate supplementation preserves stemlike characteristics, attenuates ferroptosis, and potentiates T cell–mediated antitumor immunity. Mechanistically, citraconate maintains intracellular cyclic adenosine monophosphate (cAMP) concentrations by suppressing phosphodiesterase1A/C (PDE1A/C) expression and preserving mitochondrial integrity, thereby activating protein kinase A (PKA) signaling. This activation transcriptionally represses arachidonate-5-lipoxygenase (ALOX5), consequently reducing arachidonic acid peroxidation. Clinically, diminished ALOX5 or PDE1A expression correlates with reduced T cell exhaustion and improved responses to immune checkpoint blockade (ICB) therapy. Our findings reveal the citraconate-mediated PDE1-cAMP-ALOX5 axis as a potential therapeutic target for enhancing cancer immunotherapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 119","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147820529","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}
Ronan Kapetanovic, Syeda Farhana Afroz, James E. B. Curson, Ina Kirmes, Divya Ramnath, Stephan Nothjunge, Jinting Liu, Jordan D. Atkinson, Arnaud Ahier, Karoline D. Raven, Marta Bosch, Bernhard Keller, Grace M. E. P. Lawrence, Kaustav Das Gupta, Melanie R. Shakespear, Charles Ferguson, Claudia J. Stocks, Nilesh J. Bokil, Gabriele Matthias, Tam T. K. Nguyen, Zeinab G. Khalil, Robert C. Reid, Karl A. Hansford, Philip M. Hansbro, Matthew A. Cooper, Mark A. Schembri, Antje Blumenthal, Kate Schroder, David P. Fairlie, Albert Pol, Patrick Matthias, Robert G. Parton, Steven Zuryn, Matthew J. Sweet
{"title":"Mitochondrial fission mediates an evolutionarily conserved antibacterial defense response","authors":"Ronan Kapetanovic, Syeda Farhana Afroz, James E. B. Curson, Ina Kirmes, Divya Ramnath, Stephan Nothjunge, Jinting Liu, Jordan D. Atkinson, Arnaud Ahier, Karoline D. Raven, Marta Bosch, Bernhard Keller, Grace M. E. P. Lawrence, Kaustav Das Gupta, Melanie R. Shakespear, Charles Ferguson, Claudia J. Stocks, Nilesh J. Bokil, Gabriele Matthias, Tam T. K. Nguyen, Zeinab G. Khalil, Robert C. Reid, Karl A. Hansford, Philip M. Hansbro, Matthew A. Cooper, Mark A. Schembri, Antje Blumenthal, Kate Schroder, David P. Fairlie, Albert Pol, Patrick Matthias, Robert G. Parton, Steven Zuryn, Matthew J. Sweet","doi":"10.1126/sciimmunol.aed2623","DOIUrl":"10.1126/sciimmunol.aed2623","url":null,"abstract":"<div >Animals engage pleiotropic immune defense mechanisms to survive infections. Here, we present a function for mitochondrial fission in host defense. Challenge of macrophages with <i>Escherichia coli</i> increased mitochondrial fission, with this response promoting bacterial clearance in mammalian macrophages and <i>Caenorhabditis elegans</i>. <i>E. coli</i>–induced mitochondrial fission engaged dual antibacterial responses via the mitochondrial unfolded protein response (UPR<sup>mt</sup>) and inducible lipid droplet production. Mitochondrial fission–triggered UPR<sup>mt</sup>, characterized by activation of activating transcription factor 5 (ATF5) in mouse macrophages and the paralog ATFS-1 in <i>C. elegans</i>, curtailed inducible lipid droplets to cross-regulate these pathways. The intramacrophage pathogen <i>Salmonella enterica</i> suppressed antibacterial mitochondrial fission, but restoring this response by inhibiting mitochondrial fusion–promoting histone deacetylase 6 (HDAC6) reactivated lipid droplet production and bacterial clearance. Therefore, we propose that mitochondrial fission is an ancient host defense pathway that can be exploited for anti-infective design.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 118","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147736620","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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