Olga Rivera Ballesteros, Lisa Rieble, Curtis Cai, Takuya Sekine, Vera Nilsén, Sarah Adamo, Thomas R. Müller, Christian Constantz, Julia Niessl, Eoghann White, YouBeen Ko, Tobias Kammann, Elli Mouchtaridi, Yu Gao, Akhirunnesa Mily, Elisa J. M. Raineri, Christopher Stamper, Anne Marchalot, Nicole Wild, Demi Brownlie, Sian Llewellyn-Lacey, Chris Tibbitt, Jakob Michaëlsson, Nicole Marquardt, Jenny Mjösberg, Carl Jorns, Johan K. Sandberg, Jenny Driving, David A. Price, Marcus Buggert
CXCR5+ CD8+ T cells emerged as key mediators of antiviral immunity in the context of chronic infection. However, their functional attributes and tissue distribution remain incompletely defined, especially in relation to antigen specificity. Here, we investigated the anatomical localization and antiviral properties of CXCR5+ CD8+ T cells across multiple sites throughout the human body, with an emphasis on oropharyngeal lymphoid tissues. Tonsils harbored the highest frequencies of CXCR5+ CD8+ T cells compared to other tissues, many of which expressed Granzyme K and concurrently displayed tissue residency features, as demonstrated by single cell profiling. Irrespective of clonal identity and virus specificity, CD8+ T cells expressed CXCR5 more commonly in tonsils compared to vascular circulation. CXCR5 expression was particularly prominent among tonsil-localized CD8+ T cells targeting Epstein-Barr virus (EBV) latent antigens and associated with a PD-1+ resident stem-like phenotype. These data identify a CXCR5+ tissue-resident memory CD8+ T cell subset in human tonsils with a potential role in immune surveillance of EBV.
{"title":"CXCR5 identifies stem-like resident memory CD8⁺ T cells enriched for latent EBV specificity in tonsils","authors":"Olga Rivera Ballesteros, Lisa Rieble, Curtis Cai, Takuya Sekine, Vera Nilsén, Sarah Adamo, Thomas R. Müller, Christian Constantz, Julia Niessl, Eoghann White, YouBeen Ko, Tobias Kammann, Elli Mouchtaridi, Yu Gao, Akhirunnesa Mily, Elisa J. M. Raineri, Christopher Stamper, Anne Marchalot, Nicole Wild, Demi Brownlie, Sian Llewellyn-Lacey, Chris Tibbitt, Jakob Michaëlsson, Nicole Marquardt, Jenny Mjösberg, Carl Jorns, Johan K. Sandberg, Jenny Driving, David A. Price, Marcus Buggert","doi":"10.1126/sciadv.ady8316","DOIUrl":"10.1126/sciadv.ady8316","url":null,"abstract":"<div >CXCR5<sup>+</sup> CD8<sup>+</sup> T cells emerged as key mediators of antiviral immunity in the context of chronic infection. However, their functional attributes and tissue distribution remain incompletely defined, especially in relation to antigen specificity. Here, we investigated the anatomical localization and antiviral properties of CXCR5<sup>+</sup> CD8<sup>+</sup> T cells across multiple sites throughout the human body, with an emphasis on oropharyngeal lymphoid tissues. Tonsils harbored the highest frequencies of CXCR5<sup>+</sup> CD8<sup>+</sup> T cells compared to other tissues, many of which expressed Granzyme K and concurrently displayed tissue residency features, as demonstrated by single cell profiling. Irrespective of clonal identity and virus specificity, CD8<sup>+</sup> T cells expressed CXCR5 more commonly in tonsils compared to vascular circulation. CXCR5 expression was particularly prominent among tonsil-localized CD8<sup>+</sup> T cells targeting Epstein-Barr virus (EBV) latent antigens and associated with a PD-1<sup>+</sup> resident stem-like phenotype. These data identify a CXCR5<sup>+</sup> tissue-resident memory CD8<sup>+</sup> T cell subset in human tonsils with a potential role in immune surveillance of EBV.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xintao Li, Taixia Wu, Ke Xia, Hongzhao Tang, Xuege Wang, Shudong Wang, Vincent Lyne, Ying Zu
Global forest loss increases the risk of meteorological drought by altering surface energy balances. While local impacts on temperature and precipitation are known, the extent and underlying mechanisms of its influence on meteorological drought remain unclear. Here, we analyzed 3696 paired forest loss and intact sites across boreal, temperate, and tropical zones. Forest loss intensified meteorological drought in more than 52% of affected regions. Drought prevalence in boreal zones rose by 5% over 20 years—three times greater than in tropical zones—because of reduced latent heat flux and increased surface albedo, which together suppressed convective rainfall. In contrast, tropical forests demonstrated greater ecological resilience, mitigating ~40% of meteorological drought intensification. Notably, forest loss–induced meteorological drought may further evolve into more severe agricultural and hydrological droughts. Therefore, we recommend implementing strategies tailored for each climate zone, including native forest conservation, proactive ecological restoration, and connectivity enhancement, to effectively reduce drought risk.
{"title":"Forest loss intensifies meteorological drought in more than half of Earth’s climate zones","authors":"Xintao Li, Taixia Wu, Ke Xia, Hongzhao Tang, Xuege Wang, Shudong Wang, Vincent Lyne, Ying Zu","doi":"10.1126/sciadv.adv7998","DOIUrl":"10.1126/sciadv.adv7998","url":null,"abstract":"<div >Global forest loss increases the risk of meteorological drought by altering surface energy balances. While local impacts on temperature and precipitation are known, the extent and underlying mechanisms of its influence on meteorological drought remain unclear. Here, we analyzed 3696 paired forest loss and intact sites across boreal, temperate, and tropical zones. Forest loss intensified meteorological drought in more than 52% of affected regions. Drought prevalence in boreal zones rose by 5% over 20 years—three times greater than in tropical zones—because of reduced latent heat flux and increased surface albedo, which together suppressed convective rainfall. In contrast, tropical forests demonstrated greater ecological resilience, mitigating ~40% of meteorological drought intensification. Notably, forest loss–induced meteorological drought may further evolve into more severe agricultural and hydrological droughts. Therefore, we recommend implementing strategies tailored for each climate zone, including native forest conservation, proactive ecological restoration, and connectivity enhancement, to effectively reduce drought risk.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ruoci Hu, Jooman Park, Yanyu Qian, Shaolei Xiong, Ahmad Hamza Elsabbagh, Aditya Chhikara, Huailing Fan, Zuoxiao Shi, Lifeng Liu, Yanhui Li, Zhenyuan Song, Abeer M. Mahmoud, Jiwang Chen, Joseph A. Baur, Yanlin He, Brian T. Layden, Zhenqi Zhou, Pingwen Xu, Sang-Ging Ong, Zilai Wang, Yuwei Jiang
Beige adipocytes are inducible thermogenic fat cells that emerge within white adipose tissue (WAT) in response to thermogenic stimuli and confer metabolic benefits. However, obesity impairs the generation of beige adipocytes, and the underlying mechanisms remain poorly understood. Here, we show that obesity leads to a loss of adipose progenitor cells (APCs) in WAT, accompanied by reduced estrogen (E2) levels and nicotinamide phosphoribosyltransferase (NAMPT) expression. Supplementation with E2 or nicotinamide mononucleotide (NMN), an NAMPT-derived nicotinamide adenine dinucleotide (NAD+) precursor, restores beige adipogenesis in diet-induced obese mice. Mechanistically, estrogen receptor α (ERα) in APCs is required for beige fat formation by promoting Nampt transcription. We further demonstrate that NAMPT is both necessary and sufficient to drive APC proliferation and differentiation, with interleukin-33 (IL-33) acting downstream to mediate these effects. These findings uncover a critical ERα/NAMPT/IL-33 axis that preserves progenitor function and thermogenic capacity, offering a potential therapeutic strategy to combat obesity-induced beige fat failure and associated metabolic dysfunction.
{"title":"ERα activates NAMPT/IL-33 signaling to enhance beige thermogenesis and metabolic fitness","authors":"Ruoci Hu, Jooman Park, Yanyu Qian, Shaolei Xiong, Ahmad Hamza Elsabbagh, Aditya Chhikara, Huailing Fan, Zuoxiao Shi, Lifeng Liu, Yanhui Li, Zhenyuan Song, Abeer M. Mahmoud, Jiwang Chen, Joseph A. Baur, Yanlin He, Brian T. Layden, Zhenqi Zhou, Pingwen Xu, Sang-Ging Ong, Zilai Wang, Yuwei Jiang","doi":"10.1126/sciadv.adz1385","DOIUrl":"10.1126/sciadv.adz1385","url":null,"abstract":"<div >Beige adipocytes are inducible thermogenic fat cells that emerge within white adipose tissue (WAT) in response to thermogenic stimuli and confer metabolic benefits. However, obesity impairs the generation of beige adipocytes, and the underlying mechanisms remain poorly understood. Here, we show that obesity leads to a loss of adipose progenitor cells (APCs) in WAT, accompanied by reduced estrogen (E2) levels and nicotinamide phosphoribosyltransferase (NAMPT) expression. Supplementation with E2 or nicotinamide mononucleotide (NMN), an NAMPT-derived nicotinamide adenine dinucleotide (NAD<sup>+</sup>) precursor, restores beige adipogenesis in diet-induced obese mice. Mechanistically, estrogen receptor α (ERα) in APCs is required for beige fat formation by promoting <i>Nampt</i> transcription. We further demonstrate that NAMPT is both necessary and sufficient to drive APC proliferation and differentiation, with interleukin-33 (IL-33) acting downstream to mediate these effects. These findings uncover a critical ERα/NAMPT/IL-33 axis that preserves progenitor function and thermogenic capacity, offering a potential therapeutic strategy to combat obesity-induced beige fat failure and associated metabolic dysfunction.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vector-borne plant viruses depend on insect vectors for transmission and often suppress host defenses that limit vector survival and spread. However, their impact on volatile-mediated indirect defenses remains unclear. Here, we show that rice viruses inhibit methyl salicylate (MeSA) emission, impairing parasitoid recruitment and promoting vector persistence. Field experiments demonstrate that MeSA, a key herbivore-induced volatile, suppresses vector populations by attracting egg parasitoids. Viruses counter this by targeting basic-helix-loop-helix transcription factor OsMYC2, a jasmonic acid signaling hub, thereby down-regulating OsBSMT1 and MeSA biosynthesis, responses conserved across diverse rice viruses and vector species. MeSA applications in the field restore parasitoid-mediated vector suppression, highlighting its potential for sustainable disease control. MeSA is a central ecological signal in a previously unidentified viral strategy that enhances transmission.
{"title":"Arboviruses manipulate rice’s volatile emissions, protecting insect vectors from natural enemies in the field","authors":"Qing Liu, Qian Wang, Qiong Li, Weiran Wang, Qi Li, Ziyuan Peng, Yuling Jiao, Feng Cui, Ian T. Baldwin, Xiaoming Zhang","doi":"10.1126/sciadv.aeb5215","DOIUrl":"10.1126/sciadv.aeb5215","url":null,"abstract":"<div >Vector-borne plant viruses depend on insect vectors for transmission and often suppress host defenses that limit vector survival and spread. However, their impact on volatile-mediated indirect defenses remains unclear. Here, we show that rice viruses inhibit methyl salicylate (MeSA) emission, impairing parasitoid recruitment and promoting vector persistence. Field experiments demonstrate that MeSA, a key herbivore-induced volatile, suppresses vector populations by attracting egg parasitoids. Viruses counter this by targeting basic-helix-loop-helix transcription factor OsMYC2, a jasmonic acid signaling hub, thereby down-regulating <i>OsBSMT1</i> and MeSA biosynthesis, responses conserved across diverse rice viruses and vector species. MeSA applications in the field restore parasitoid-mediated vector suppression, highlighting its potential for sustainable disease control. MeSA is a central ecological signal in a previously unidentified viral strategy that enhances transmission.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sean Coakley, Igor Bonacossa-Pereira, Dat Le, Massimo A. Hilliard
Spectrins are highly conserved molecules that form a distinct membrane-associated periodic scaffold within axons to provide mechanical resilience. In Caenorhabditis elegans, UNC-70/ß-Spectrin also functions within the epidermis to maintain the integrity of sensory neurons. The precise molecular organization in this tissue and the cellular mechanisms that mediate this protection are unknown. Here, using three-dimensional structured illumination microscopy, we show that epidermal SPC-1/α-Spectrin and UNC-70/ß-Spectrin form a crescent-shaped scaffold with a periodicity of ~200 nm that embraces adjacent axons. This epidermal Spectrin scaffold is induced by developing axons and reformed during axonal regeneration, creating a “molecular imprint” of the nervous system. Disruption of this epidermal scaffold causes axonal damage, and we propose that it protects axons by restricting the endocytosis of cell adhesion molecules required for axonal-epidermal adhesion. Our findings reveal a distinct periodic Spectrin scaffold within the epidermis that is molded by the developing nervous system and protects axons from damage.
{"title":"An epidermal membrane-associated periodic skeleton restricts endocytosis to stabilize neuron-epidermal attachment and preserve axons","authors":"Sean Coakley, Igor Bonacossa-Pereira, Dat Le, Massimo A. Hilliard","doi":"10.1126/sciadv.adz4762","DOIUrl":"10.1126/sciadv.adz4762","url":null,"abstract":"<div >Spectrins are highly conserved molecules that form a distinct membrane-associated periodic scaffold within axons to provide mechanical resilience. In <i>Caenorhabditis elegans</i>, UNC-70/ß-Spectrin also functions within the epidermis to maintain the integrity of sensory neurons. The precise molecular organization in this tissue and the cellular mechanisms that mediate this protection are unknown. Here, using three-dimensional structured illumination microscopy, we show that epidermal SPC-1/α-Spectrin and UNC-70/ß-Spectrin form a crescent-shaped scaffold with a periodicity of ~200 nm that embraces adjacent axons. This epidermal Spectrin scaffold is induced by developing axons and reformed during axonal regeneration, creating a “molecular imprint” of the nervous system. Disruption of this epidermal scaffold causes axonal damage, and we propose that it protects axons by restricting the endocytosis of cell adhesion molecules required for axonal-epidermal adhesion. Our findings reveal a distinct periodic Spectrin scaffold within the epidermis that is molded by the developing nervous system and protects axons from damage.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juha Aalto, Matti Kämäräinen, Mika Rantanen, Pekka Niittynen, Gareth K. Phoenix, Jonathan Lenoir, Ilya Maclean, Miska Luoto
The Arctic climate is rapidly warming, but long-term changes in extreme weather events that cause major ecosystem disturbances are not well understood. Here, by using a state-of-the-art atmospheric reanalysis spanning the past seven decades, we show that, in many parts of the terrestrial Arctic, the frequency of extreme weather events has increased sharply. We found pronounced spatial variability in bioclimatic extremes during the past 30 years, including more droughts in the high-Arctic and greater area affected by winter-warming and rain-on-snow events, especially in the European Arctic region. Across one-third of the Arctic domain, such extreme events have only recently begun to occur. Thus, the Arctic is entering a novel era of bioclimatic extremes with likely severe consequences on cold ecosystems.
{"title":"A new era of bioclimatic extremes in the terrestrial Arctic","authors":"Juha Aalto, Matti Kämäräinen, Mika Rantanen, Pekka Niittynen, Gareth K. Phoenix, Jonathan Lenoir, Ilya Maclean, Miska Luoto","doi":"10.1126/sciadv.adw5698","DOIUrl":"10.1126/sciadv.adw5698","url":null,"abstract":"<div >The Arctic climate is rapidly warming, but long-term changes in extreme weather events that cause major ecosystem disturbances are not well understood. Here, by using a state-of-the-art atmospheric reanalysis spanning the past seven decades, we show that, in many parts of the terrestrial Arctic, the frequency of extreme weather events has increased sharply. We found pronounced spatial variability in bioclimatic extremes during the past 30 years, including more droughts in the high-Arctic and greater area affected by winter-warming and rain-on-snow events, especially in the European Arctic region. Across one-third of the Arctic domain, such extreme events have only recently begun to occur. Thus, the Arctic is entering a novel era of bioclimatic extremes with likely severe consequences on cold ecosystems.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vivian Jou, Scott D. Semelsberger, Jack Smerczynski, Jessica A. Lehoczky
The distal mouse digit tip regenerates postamputation, while the proximal digit undergoes fibrosis. This study presents a comparative single-cell RNA sequencing–based analysis of regenerating and nonregenerating digits to computationally identify fibroblast subpopulations and genes associated with fibrosis and regeneration. To test the sufficiency of identified candidate genes to alter wound healing outcomes, we developed a robust adeno-associated virus gene delivery technique for digit fibroblasts. We found that overexpression of candidate profibrotic gene Pcolce2 or Prelp in the blastema modifies normal regeneration and overexpression of candidate proregenerative factor Ccl2 or Mest in the proximal digit substantially increases bone deposition. These data demonstrate that the computational analysis combined with the AAV delivery approach presented in this study provides a powerful framework for identifying the driving factors of fibrosis and regeneration in the mammalian digit.
{"title":"Mouse digit AAV gene delivery into fibroblasts regulates regenerative outcome","authors":"Vivian Jou, Scott D. Semelsberger, Jack Smerczynski, Jessica A. Lehoczky","doi":"10.1126/sciadv.adz0229","DOIUrl":"10.1126/sciadv.adz0229","url":null,"abstract":"<div >The distal mouse digit tip regenerates postamputation, while the proximal digit undergoes fibrosis. This study presents a comparative single-cell RNA sequencing–based analysis of regenerating and nonregenerating digits to computationally identify fibroblast subpopulations and genes associated with fibrosis and regeneration. To test the sufficiency of identified candidate genes to alter wound healing outcomes, we developed a robust adeno-associated virus gene delivery technique for digit fibroblasts. We found that overexpression of candidate profibrotic gene <i>Pcolce2</i> or <i>Prelp</i> in the blastema modifies normal regeneration and overexpression of candidate proregenerative factor <i>Ccl2</i> or <i>Mest</i> in the proximal digit substantially increases bone deposition. These data demonstrate that the computational analysis combined with the AAV delivery approach presented in this study provides a powerful framework for identifying the driving factors of fibrosis and regeneration in the mammalian digit.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The CD4+ cytotoxic T lymphocytes (CD4-CTLs) with cytotoxic potential are reported to be the components of protective immune response in many diseases. However, the lack of understanding about their lineage, molecular character, and cytolytic potential in comparison to CD8+(CD8)-CTLs has restricted their utility. Thus, here, by parallelly analyzing the human peripheral CD4-CTLs and CD8-CTLs, we demonstrate that they are indistinguishable for the cytotoxic program. Furthermore, using an integrative multiomics approach combining the transcriptome, T cell antigen-receptor repertoire, and open chromatin profile of CD4+ T cell memory subsets, we found a stem-cell memory subset that is precommitted to the cytotoxicity program. Through an in vitro differentiation model, we developed CD4+ T cells with cytolytic potential coexpressing and exhibiting progressive chromatin accessibility for cytotoxicity- and longevity-associated genes, hence generating long-lived CD4-CTL effectors of varying cytotoxic capacity. Together, our study advocates for exploring both CD4-CTLs and CD8-CTLs for vaccine development, vaccine efficacy testing, and immunotherapies and cell-based therapies for precision medicine.
{"title":"A distinct subset of stem-cell memory is poised for the cytotoxicity program in CD4+ T cells in humans","authors":"Raunak Kar, Shreya Sinha, Zainab Khatun, Anjali Sharma, Veena S. Patil","doi":"10.1126/sciadv.ady6423","DOIUrl":"10.1126/sciadv.ady6423","url":null,"abstract":"<div >The CD4<sup>+</sup> cytotoxic T lymphocytes (CD4-CTLs) with cytotoxic potential are reported to be the components of protective immune response in many diseases. However, the lack of understanding about their lineage, molecular character, and cytolytic potential in comparison to CD8<sup>+</sup>(CD8)-CTLs has restricted their utility. Thus, here, by parallelly analyzing the human peripheral CD4-CTLs and CD8-CTLs, we demonstrate that they are indistinguishable for the cytotoxic program. Furthermore, using an integrative multiomics approach combining the transcriptome, T cell antigen-receptor repertoire, and open chromatin profile of CD4<sup>+</sup> T cell memory subsets, we found a stem-cell memory subset that is precommitted to the cytotoxicity program. Through an in vitro differentiation model, we developed CD4<sup>+</sup> T cells with cytolytic potential coexpressing and exhibiting progressive chromatin accessibility for cytotoxicity- and longevity-associated genes, hence generating long-lived CD4-CTL effectors of varying cytotoxic capacity. Together, our study advocates for exploring both CD4-CTLs and CD8-CTLs for vaccine development, vaccine efficacy testing, and immunotherapies and cell-based therapies for precision medicine.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Epigenetic regulation is crucial for balancing hematopoietic stem cell (HSC) self-renewal and differentiation, thereby maintaining hematopoietic homeostasis. Although Nat10-mediated RNA ac4C modification has been implicated in malignant hematopoiesis, its role in normal hematopoiesis remains unexplored. Here, we developed ULAC-seq to map ac4C in rare hematopoietic stem/progenitor cells (HSPCs) and revealed dynamic, cell-type–specific ac4C patterns, peaking in megakaryocyte-erythroid progenitors (MEPs), correlating with elevated Nat10 expression. Nat10 knockout disrupts HSC self-renewal and arrests MEP differentiation, leading to fetal and postnatal hematopoietic failure. Mechanistically, Nat10 deposits ac4C on mRNAs encoding key hematopoietic transcription regulators (e.g., Nfix), thereby enhancing their translation. Nat10 loss reduces Nfix protein levels and suppresses expression of its target genes (e.g., Mpl) that govern HSPC fate, while Nfix reconstitution rescues colony-forming defects in Nat10-null HSPCs. Our findings reveal that Nat10 orchestrates hematopoiesis through ac4C-dependent translational control of transcriptional factors, establishing an epitranscriptome-transcriptome regulatory axis essential for HSC maintenance and function.
{"title":"Nat10-mediated ac4C epitranscriptomics orchestrates hematopoietic stem/progenitor cell fate determination via translation control","authors":"Feng Huang, Yushuai Wang, Weiwei Gao, Xiuxin Zhang, Jiajia Zhou, Ying Yang, Hongjie Mo, Minhan Wang, Qi Chen, Guangdun Peng, Jianjun Chen, Huilin Huang, Hengyou Weng","doi":"10.1126/sciadv.ady0301","DOIUrl":"10.1126/sciadv.ady0301","url":null,"abstract":"<div >Epigenetic regulation is crucial for balancing hematopoietic stem cell (HSC) self-renewal and differentiation, thereby maintaining hematopoietic homeostasis. Although Nat10-mediated RNA ac4C modification has been implicated in malignant hematopoiesis, its role in normal hematopoiesis remains unexplored. Here, we developed ULAC-seq to map ac4C in rare hematopoietic stem/progenitor cells (HSPCs) and revealed dynamic, cell-type–specific ac4C patterns, peaking in megakaryocyte-erythroid progenitors (MEPs), correlating with elevated Nat10 expression. Nat10 knockout disrupts HSC self-renewal and arrests MEP differentiation, leading to fetal and postnatal hematopoietic failure. Mechanistically, Nat10 deposits ac4C on mRNAs encoding key hematopoietic transcription regulators (e.g., Nfix), thereby enhancing their translation. Nat10 loss reduces Nfix protein levels and suppresses expression of its target genes (e.g., Mpl) that govern HSPC fate, while Nfix reconstitution rescues colony-forming defects in Nat10-null HSPCs. Our findings reveal that Nat10 orchestrates hematopoiesis through ac4C-dependent translational control of transcriptional factors, establishing an epitranscriptome-transcriptome regulatory axis essential for HSC maintenance and function.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Eleonora Rossi, Joseph N. Keating, Nathan J. Kenny, Mattia Giacomelli, Sandra Álvarez-Carretero, Astrid Schuster, Paco Cárdenas, Sergi Taboada, Vasiliki Koutsouveli, Philip C. J. Donoghue, Ana Riesgo, Davide Pisani
Sponges (Porifera) are ecosystem engineers that play a critical role in global biogeochemical processes. Their evolution is key to understanding Neoproterozoic paleoecology but remains mired in controversy. Molecular timescales suggest a Tonian or Cryogenian origin, while their oldest unequivocal fossils consist of disarticulated siliceous spicules from the Late Ediacaran. We derived a new, dated sponge phylogeny and tested whether ancestral sponges had mineralized skeletons. We resolve the sponge phylogeny in good agreement with current knowledge and date their origin to the early Ediacaran. Our results suggest that early sponges were not biomineralized and that both biosilicification and biocalcification evolved independently multiple times across Porifera. We reconcile fossil evidence and molecular estimates of sponge evolution by showing that the Neoproterozoic history of Porifera is limited to the Ediacaran and providing evidence suggesting that sponges are largely absent from the Ediacaran record because they were yet to evolve biomineralized skeletons.
{"title":"Independent origins of spicules reconcile paleontological and molecular evidence of sponge evolutionary history","authors":"Maria Eleonora Rossi, Joseph N. Keating, Nathan J. Kenny, Mattia Giacomelli, Sandra Álvarez-Carretero, Astrid Schuster, Paco Cárdenas, Sergi Taboada, Vasiliki Koutsouveli, Philip C. J. Donoghue, Ana Riesgo, Davide Pisani","doi":"10.1126/sciadv.adx1754","DOIUrl":"10.1126/sciadv.adx1754","url":null,"abstract":"<div >Sponges (Porifera) are ecosystem engineers that play a critical role in global biogeochemical processes. Their evolution is key to understanding Neoproterozoic paleoecology but remains mired in controversy. Molecular timescales suggest a Tonian or Cryogenian origin, while their oldest unequivocal fossils consist of disarticulated siliceous spicules from the Late Ediacaran. We derived a new, dated sponge phylogeny and tested whether ancestral sponges had mineralized skeletons. We resolve the sponge phylogeny in good agreement with current knowledge and date their origin to the early Ediacaran. Our results suggest that early sponges were not biomineralized and that both biosilicification and biocalcification evolved independently multiple times across Porifera. We reconcile fossil evidence and molecular estimates of sponge evolution by showing that the Neoproterozoic history of Porifera is limited to the Ediacaran and providing evidence suggesting that sponges are largely absent from the Ediacaran record because they were yet to evolve biomineralized skeletons.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"12 2","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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