Pub Date : 2025-11-07DOI: 10.1126/sciimmunol.adm7800
Martina Zoccheddu, Kensuke Suga, Amara Seng, Mattias N. D. Svensson, Paramita Dutta, Sanaz Panahandeh, Hadijat-Kubura Moradeke Makinde, Myungja Ro, Yizhou Wang, Hyobin Kim, Zbigniew Mikulski, Katarzyna Dobaczewska, Francesca Ingegnoli, Ruth Minsha, John F. Seagrist, Mary Carns, Kathleen Aren, Salina Dominguez, Mohammad Daud Khan, Angela Denn, Roberto Caporali, Pietro Simone Randelli, David A. McBride, Arthur M. Mandelin II, Carla Marie Cuda, Zhiping Paul Wang, Jason H. Moore, Nisarg J. Shah, Kyoung Jae Won, Deborah R. Winter, Ferhat Ay, Harris Perlman, Nunzio Bottini
T helper 17 (TH17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce TH17 cell transdifferentiation into IL-17–negative exTH17 cells, but the role of exTH17 cells in arthritis is unknown. We performed TH17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial TH17 cells transdifferentiate into CD44+ exTH17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exTH17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4+ T cells. We demonstrate that cross-talk between TH17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes TH17-exTH17 cell conversion. CD44 is necessary for exTH17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes TH17-exTH17 cell conversion. These results could potentially enable RA precision therapy.
类风湿关节炎（RA）患者的外周和滑膜中发现T辅助17 （ht17）细胞；然而，针对il -17的干预措施对已建立的RA的疗效有限。炎症可诱导T H 17细胞转分化为il -17阴性的exT H 17细胞，但exT H 17细胞在关节炎中的作用尚不清楚。我们在类风湿关节炎的SKG小鼠模型中进行了ht17细胞谱系追踪。在关节炎小鼠中，滑膜ht17细胞转分化为CD44 + exT h17细胞，后者更具有关节炎性，并维持不依赖IL-17的炎症。exT h17细胞基因特征包括CD44和鞘氨醇-1-磷酸受体4 （S1PR4）的上调，并与人RA滑膜CD4 + T细胞的谱相关。我们证明了th17细胞和成纤维细胞样滑膜细胞（FLSs）之间通过S1P的相互作用促进了th17 - ext h17细胞的转化。CD44对于exT h17细胞介导的关节炎是必需的。我们的研究表明，在RA进展过程中FLS的扩增促进了ht17 - ext h17细胞的转化。这些结果可能使RA精确治疗成为可能。
{"title":"TH17 cells converted into exTH17 cells sustain rheumatoid-like IL-17–independent inflammatory arthritis","authors":"Martina Zoccheddu, Kensuke Suga, Amara Seng, Mattias N. D. Svensson, Paramita Dutta, Sanaz Panahandeh, Hadijat-Kubura Moradeke Makinde, Myungja Ro, Yizhou Wang, Hyobin Kim, Zbigniew Mikulski, Katarzyna Dobaczewska, Francesca Ingegnoli, Ruth Minsha, John F. Seagrist, Mary Carns, Kathleen Aren, Salina Dominguez, Mohammad Daud Khan, Angela Denn, Roberto Caporali, Pietro Simone Randelli, David A. McBride, Arthur M. Mandelin II, Carla Marie Cuda, Zhiping Paul Wang, Jason H. Moore, Nisarg J. Shah, Kyoung Jae Won, Deborah R. Winter, Ferhat Ay, Harris Perlman, Nunzio Bottini","doi":"10.1126/sciimmunol.adm7800","DOIUrl":"10.1126/sciimmunol.adm7800","url":null,"abstract":"<div >T helper 17 (T<sub>H</sub>17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce T<sub>H</sub>17 cell transdifferentiation into IL-17–negative exT<sub>H</sub>17 cells, but the role of exT<sub>H</sub>17 cells in arthritis is unknown. We performed T<sub>H</sub>17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial T<sub>H</sub>17 cells transdifferentiate into CD44<sup>+</sup> exT<sub>H</sub>17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exT<sub>H</sub>17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4<sup>+</sup> T cells. We demonstrate that cross-talk between T<sub>H</sub>17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes T<sub>H</sub>17-exT<sub>H</sub>17 cell conversion. CD44 is necessary for exT<sub>H</sub>17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes T<sub>H</sub>17-exT<sub>H</sub>17 cell conversion. These results could potentially enable RA precision therapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 113","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455363","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}
Pub Date : 2025-10-31DOI: 10.1126/sciimmunol.adw1992
Kevin Man, Vinicius A. Duarte da Silva, Nikita Potemkin, Sarah S. Gabriel, Teisha Mason, Tarek Elmzzahi, Marcela De Lima Moreira, Chun-Hsi Su, Laura Mackay, Marc D. Beyer, Jan Schröder, Georg Gasteiger, Axel Kallies
Tissue-resident memory T (TRM) cells provide localized immunity against intracellular pathogens and cancer. Upon antigen reencounter, TRM cells differentiate into effector cells while also giving rise to another generation of memory cells. Here, we show that intestinal TRM cells that express the transcriptional regulators TCF1 or ID3 exhibit stem-like memory properties and are endowed with a superior capacity to regenerate effector and memory T cells after pathogen reencounter. Ablation of TCF1 using a TRM cell–specific mouse model resulted in impaired formation of intestinal TRM cells, altered their transcriptional heterogeneity, and increased their differentiation into tissue-confined and recirculating CX3CR1+ effector cells during recall. TGF-β and retinoic acid were required for formation and survival of TCF1- and ID3-expressing TRM cells and restrained their differentiation into CX3CR1+ effector cells during reinfection. Thus, stem-like cells control the quality and recall capacity of TRM cells, thereby contributing to anamnestic memory responses.
{"title":"Stem-like tissue-resident memory T cells control functional heterogeneity and reactivation of T cell memory in the intestine","authors":"Kevin Man, Vinicius A. Duarte da Silva, Nikita Potemkin, Sarah S. Gabriel, Teisha Mason, Tarek Elmzzahi, Marcela De Lima Moreira, Chun-Hsi Su, Laura Mackay, Marc D. Beyer, Jan Schröder, Georg Gasteiger, Axel Kallies","doi":"10.1126/sciimmunol.adw1992","DOIUrl":"10.1126/sciimmunol.adw1992","url":null,"abstract":"<div >Tissue-resident memory T (T<sub>RM</sub>) cells provide localized immunity against intracellular pathogens and cancer. Upon antigen reencounter, T<sub>RM</sub> cells differentiate into effector cells while also giving rise to another generation of memory cells. Here, we show that intestinal T<sub>RM</sub> cells that express the transcriptional regulators TCF1 or ID3 exhibit stem-like memory properties and are endowed with a superior capacity to regenerate effector and memory T cells after pathogen reencounter. Ablation of TCF1 using a T<sub>RM</sub> cell–specific mouse model resulted in impaired formation of intestinal T<sub>RM</sub> cells, altered their transcriptional heterogeneity, and increased their differentiation into tissue-confined and recirculating CX3CR1<sup>+</sup> effector cells during recall. TGF-β and retinoic acid were required for formation and survival of TCF1- and ID3-expressing T<sub>RM</sub> cells and restrained their differentiation into CX3CR1<sup>+</sup> effector cells during reinfection. Thus, stem-like cells control the quality and recall capacity of T<sub>RM</sub> cells, thereby contributing to anamnestic memory responses.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145405217","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}
Pub Date : 2025-10-31DOI: 10.1126/sciimmunol.adu3718
Fiamma Salerno, Alex J. Whale, Louise S. Matheson, Davide Vespasiani, William S. Foster, Twm J. Mitchell, Michael Screen, Melanie Stammers, Sarah E. Bell, Daniel J. Hodson, Hamish W. King, Michelle A. Linterman, Jonathan Houseley, Martin Turner
The germinal center (GC) reaction drives the production of high-affinity antibodies by iterative cycles of B cell somatic hypermutation, selection, and proliferation. How GC B cells undergo rapid cell division while maintaining genome stability is poorly understood. Here, we show that the RNA binding proteins ZFP36L1 and ZFP36L2 act downstream of antigen sensing and protect GC B cells from replication stress by controlling a cell cycle–related posttranscriptional regulon. They safeguard the successful completion of mitosis by balancing CDK1 and p21-mediated regulation of cell-cycle progression. In their absence, GC B cells are prone to arrest in the G2-M phase and die by apoptosis, resulting in curtailed GC responses. DNA replication forks stalled at active replication initiation zones, causing replication stress and increased activity of the ATR-CHK1 DNA damage response. Thus, RNA binding proteins guide posttranscriptional gene regulation and maintain a functional G2-M checkpoint in GC B cells.
{"title":"RNA binding proteins control the G2-M checkpoint of the germinal center B cell","authors":"Fiamma Salerno, Alex J. Whale, Louise S. Matheson, Davide Vespasiani, William S. Foster, Twm J. Mitchell, Michael Screen, Melanie Stammers, Sarah E. Bell, Daniel J. Hodson, Hamish W. King, Michelle A. Linterman, Jonathan Houseley, Martin Turner","doi":"10.1126/sciimmunol.adu3718","DOIUrl":"10.1126/sciimmunol.adu3718","url":null,"abstract":"<div >The germinal center (GC) reaction drives the production of high-affinity antibodies by iterative cycles of B cell somatic hypermutation, selection, and proliferation. How GC B cells undergo rapid cell division while maintaining genome stability is poorly understood. Here, we show that the RNA binding proteins ZFP36L1 and ZFP36L2 act downstream of antigen sensing and protect GC B cells from replication stress by controlling a cell cycle–related posttranscriptional regulon. They safeguard the successful completion of mitosis by balancing CDK1 and p21-mediated regulation of cell-cycle progression. In their absence, GC B cells are prone to arrest in the G<sub>2</sub>-M phase and die by apoptosis, resulting in curtailed GC responses. DNA replication forks stalled at active replication initiation zones, causing replication stress and increased activity of the ATR-CHK1 DNA damage response. Thus, RNA binding proteins guide posttranscriptional gene regulation and maintain a functional G<sub>2</sub>-M checkpoint in GC B cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145405215","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}
Pub Date : 2025-10-31DOI: 10.1126/sciimmunol.adx1135
Saya Satoh, Yaw Bia Tan, Benjamin Heil, Shintaro Yamada, Verena Schütte, Celest Phang, Chaozhi Tang, Yuta Tsukamoto, Takahiro Higuchi, Takashi Fujita, Rayk Behrendt, Martin Schlee, Dahai Luo, Hiroki Kato
Detecting viral RNA by the ubiquitously expressed cytosolic receptor retinoic acid–inducible gene I (RIG-I) is critical for antiviral immune responses, including type I interferon (IFN-I) and chemokine induction. RIG-I has evolved to sensitively recognize viral RNA but tolerate self-RNA. RIG-I mutations causing self-tolerance loss induce IFN-I and chemokines in patients, initiating autoinflammation. We observed that mice expressing the RIG-I patient variant E373A spontaneously developed lupus-like nephritis. Kidney-derived chemokines attracted monocytes through CCR2 (C-C motif chemokine receptor 2) and induced interstitial inflammation and tubular damage. This led to renal dysfunction independently of immunoglobulin G–nucleic acid complex deposition. Sequencing of RIG-I E373A–bound RNA from kidney-derived cells identified short noncoding Y-RNA. Deletion of the most enriched Y-RNA species reduced RIG-I E373A–induced IFN-I responses. Cryo–electron microscopy and molecular analyses revealed that RIG-I E373A binding to the Y-RNA stem region resulted in its activation. Thus, we demonstrate that Y-RNA activates a RIG-I gain-of-function mutant in a tissue-specific manner, causing autoinflammation culminating in lupus nephritis.
{"title":"Local activation of mutant RIG-I by short noncoding Y-RNA in the kidney triggers lethal nephritis","authors":"Saya Satoh, Yaw Bia Tan, Benjamin Heil, Shintaro Yamada, Verena Schütte, Celest Phang, Chaozhi Tang, Yuta Tsukamoto, Takahiro Higuchi, Takashi Fujita, Rayk Behrendt, Martin Schlee, Dahai Luo, Hiroki Kato","doi":"10.1126/sciimmunol.adx1135","DOIUrl":"10.1126/sciimmunol.adx1135","url":null,"abstract":"<div >Detecting viral RNA by the ubiquitously expressed cytosolic receptor retinoic acid–inducible gene I (RIG-I) is critical for antiviral immune responses, including type I interferon (IFN-I) and chemokine induction. RIG-I has evolved to sensitively recognize viral RNA but tolerate self-RNA. RIG-I mutations causing self-tolerance loss induce IFN-I and chemokines in patients, initiating autoinflammation. We observed that mice expressing the RIG-I patient variant E373A spontaneously developed lupus-like nephritis. Kidney-derived chemokines attracted monocytes through CCR2 (C-C motif chemokine receptor 2) and induced interstitial inflammation and tubular damage. This led to renal dysfunction independently of immunoglobulin G–nucleic acid complex deposition. Sequencing of RIG-I E373A–bound RNA from kidney-derived cells identified short noncoding Y-RNA. Deletion of the most enriched Y-RNA species reduced RIG-I E373A–induced IFN-I responses. Cryo–electron microscopy and molecular analyses revealed that RIG-I E373A binding to the Y-RNA stem region resulted in its activation. Thus, we demonstrate that Y-RNA activates a RIG-I gain-of-function mutant in a tissue-specific manner, causing autoinflammation culminating in lupus nephritis.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145405216","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}
A unique subpopulation of memory T helper 2 (TH2) cells expressing the interleukin-33 (IL-33) receptor ST2 drives allergic disease pathogenesis. However, the immunometabolic mechanisms that induce ST2hi memory TH2 cells remain unclear. We show using a mouse model of chronic allergic airway inflammation that long-chain unsaturated fatty acids (LC-UFAs) accumulate in the inflammatory milieu during chronic airway inflammation. Activated TH2 cells take up LC-UFAs, transiently store them in lipid droplets (LDs), and catabolize LDs through lipolysis and microlipophagy. LD catabolism regulated by adipose triglyceride lipase (ATGL) activates peroxisome proliferator–activated receptor γ (PPARγ). PPARγ then binds the Il1rl1 locus encoding ST2 and induces ST2hi effector and memory TH2 cells. In eosinophilic chronic rhinosinusitis, CD45RO+ CD4 T cells in nasal polyps exhibit microlipophagy and an accessible IL1RL1 enhancer, indicating that these mechanisms are conserved in humans. Thus, the storage and catabolism of inflammatory milieu–derived LC-UFAs direct pathogenic adaptive type 2 immunity, offering potential therapeutic strategies for persistent allergic inflammation.
{"title":"Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity","authors":"Hiroyuki Yagyu, Masahiro Kiuchi, Atsushi Sasaki, Eisuke Itakura, Kota Kokubo, Chiaki Iwamura, Atsushi Onodera, Ami Aoki, Takahisa Hishiya, Kaori Tsuji, Takuto Hiramoto, Rie Shinmi, Yuri Sonobe, Takahiro Arano, Kanae Ohishi, Shigenori Baba, Junya Kurita, Tomohisa Iinuma, Syuji Yonekura, Yu Hara, Motoko Y. Kimura, Shinichiro Motohashi, Damon J. Tumes, Toyoyuki Hanazawa, Takeshi Kaneko, Toshinori Nakayama, Kiyoshi Hirahara","doi":"10.1126/sciimmunol.adp0849","DOIUrl":"10.1126/sciimmunol.adp0849","url":null,"abstract":"<div >A unique subpopulation of memory T helper 2 (T<sub>H</sub>2) cells expressing the interleukin-33 (IL-33) receptor ST2 drives allergic disease pathogenesis. However, the immunometabolic mechanisms that induce ST2<sup>hi</sup> memory T<sub>H</sub>2 cells remain unclear. We show using a mouse model of chronic allergic airway inflammation that long-chain unsaturated fatty acids (LC-UFAs) accumulate in the inflammatory milieu during chronic airway inflammation. Activated T<sub>H</sub>2 cells take up LC-UFAs, transiently store them in lipid droplets (LDs), and catabolize LDs through lipolysis and microlipophagy. LD catabolism regulated by adipose triglyceride lipase (ATGL) activates peroxisome proliferator–activated receptor γ (PPARγ). PPARγ then binds the <i>Il1rl1</i> locus encoding ST2 and induces ST2<sup>hi</sup> effector and memory T<sub>H</sub>2 cells. In eosinophilic chronic rhinosinusitis, CD45RO<sup>+</sup> CD4 T cells in nasal polyps exhibit microlipophagy and an accessible <i>IL1RL1</i> enhancer, indicating that these mechanisms are conserved in humans. Thus, the storage and catabolism of inflammatory milieu–derived LC-UFAs direct pathogenic adaptive type 2 immunity, offering potential therapeutic strategies for persistent allergic inflammation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145352991","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}
Pub Date : 2025-10-24DOI: 10.1126/sciimmunol.ads9456
Jordy Saravia, Nicole M. Chapman, Yu Sun, Xiaoxi Meng, Isabel Risch, Wei Li, Cliff Guy, Hao Shi, Haoran Hu, Yogesh Dhungana, Jia Li, Zhiyuan You, Anil KC, Seon Ah Lim, Jana L. Raynor, Sharad Shrestha, Erienne G. Norton, Sarah E. La Grange, Camenzind G. Robinson, Peter Vogel, Hongbo Chi
Immunotherapies targeting regulatory T (Treg) cells often trigger inflammation and autoimmunity. How Treg cells undergo functional reprogramming to reestablish immune homeostasis under these conditions remains unclear. Here, we demonstrate that mitochondrial and lysosomal signaling orchestrates Treg cell metabolic and functional fitness. Treg cell–specific loss of the mitochondrial protein Opa1 led to disrupted immune homeostasis and pronounced inflammation, and reduced the generation of Treg cells with high mitochondrial metabolic and suppressive function. Opa1 deletion triggered mitochondrial bioenergetic stress, associated with increased adenosine monophosphate–activated protein kinase (AMPK) signaling and transcription factor EB (TFEB) activation. Further, Treg cell–specific deletion of the lysosomal signaling protein Flcn partially phenocopied Opa1 deficiency–associated inflammation and aberrant TFEB activation, and these effects were rectified by TFEB codeletion. Flcn-deficient Treg cells were enriched in a terminal “metabolic quiescence reset” state and failed to accumulate in nonlymphoid tissues and suppress antitumor immunity. Our study demonstrates that organelle-directed metabolic and signaling processes and mitochondria–lysosome interplay control Treg cell differentiation and function.
{"title":"Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells","authors":"Jordy Saravia, Nicole M. Chapman, Yu Sun, Xiaoxi Meng, Isabel Risch, Wei Li, Cliff Guy, Hao Shi, Haoran Hu, Yogesh Dhungana, Jia Li, Zhiyuan You, Anil KC, Seon Ah Lim, Jana L. Raynor, Sharad Shrestha, Erienne G. Norton, Sarah E. La Grange, Camenzind G. Robinson, Peter Vogel, Hongbo Chi","doi":"10.1126/sciimmunol.ads9456","DOIUrl":"10.1126/sciimmunol.ads9456","url":null,"abstract":"<div >Immunotherapies targeting regulatory T (T<sub>reg</sub>) cells often trigger inflammation and autoimmunity. How T<sub>reg</sub> cells undergo functional reprogramming to reestablish immune homeostasis under these conditions remains unclear. Here, we demonstrate that mitochondrial and lysosomal signaling orchestrates T<sub>reg</sub> cell metabolic and functional fitness. T<sub>reg</sub> cell–specific loss of the mitochondrial protein Opa1 led to disrupted immune homeostasis and pronounced inflammation, and reduced the generation of T<sub>reg</sub> cells with high mitochondrial metabolic and suppressive function. Opa1 deletion triggered mitochondrial bioenergetic stress, associated with increased adenosine monophosphate–activated protein kinase (AMPK) signaling and transcription factor EB (TFEB) activation. Further, T<sub>reg</sub> cell–specific deletion of the lysosomal signaling protein Flcn partially phenocopied Opa1 deficiency–associated inflammation and aberrant TFEB activation, and these effects were rectified by TFEB codeletion. Flcn-deficient T<sub>reg</sub> cells were enriched in a terminal “metabolic quiescence reset” state and failed to accumulate in nonlymphoid tissues and suppress antitumor immunity. Our study demonstrates that organelle-directed metabolic and signaling processes and mitochondria–lysosome interplay control T<sub>reg</sub> cell differentiation and function.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145352990","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}
Pub Date : 2025-10-17DOI: 10.1126/sciimmunol.adu7961
Zhenfei Xie, Xuesong Wang, Yu Yan, Jon M. Steichen, Krystal M. Ma, Christopher A. Cottrell, Eleonora Melzi, Maria Bottermann, Paula Maldonado Villavicencio, Kimmo Rantalainen, Torben Schiffner, John E. Warner, Stephanie R. Weldon, Thavaleak Prum, Jordan R. Ellis-Pugh, Jonathan L. Torres, Abigail M. Jackson, Claudia T. Flynn, Gabriel Ozorowski, Sunny Himansu, Andrea Carfi, Andrew B. Ward, Usha Nair, William R. Schief, Facundo D. Batista
Germline-targeting is a promising approach to HIV vaccine development that begins with the elicitation of precursors to broadly neutralizing antibodies (bnAbs), but it remains unclear whether simultaneous elicitation of precursors to multiple epitopes on the HIV envelope (Env) would be inhibited by competition. This study used preclinical mouse models with physiologically relevant frequencies of bnAb precursor–bearing B cells to compare precursor elicitation by coadministration of multiple protein or mRNA lipid nanoparticle (mRNA-LNP) germline-targeting immunogens. These immunogens activate multiple bnAb precursor classes targeting distinct epitopes on Env but with evidence of potential competition. Simultaneous delivery of immunogens encoded by mRNA-LNPs, however, drove maturation across different precursor frequencies and immunogen doses. Furthermore, administration of a cocktail of mRNA-LNP immunogens (N332-GT5 gp151, ApexGT5 gp151, eOD-GT8 60mer, and 10E8-GT12 24mer) led to balanced activation of four distinct bnAb precursor classes, indicating that multiepitope HIV bnAb precursor priming might be successfully implemented in humans but might be immunogen dependent.
{"title":"Simultaneous priming of HIV broadly neutralizing antibody precursors to multiple epitopes by germline-targeting mRNA-LNP immunogens in mouse models","authors":"Zhenfei Xie, Xuesong Wang, Yu Yan, Jon M. Steichen, Krystal M. Ma, Christopher A. Cottrell, Eleonora Melzi, Maria Bottermann, Paula Maldonado Villavicencio, Kimmo Rantalainen, Torben Schiffner, John E. Warner, Stephanie R. Weldon, Thavaleak Prum, Jordan R. Ellis-Pugh, Jonathan L. Torres, Abigail M. Jackson, Claudia T. Flynn, Gabriel Ozorowski, Sunny Himansu, Andrea Carfi, Andrew B. Ward, Usha Nair, William R. Schief, Facundo D. Batista","doi":"10.1126/sciimmunol.adu7961","DOIUrl":"10.1126/sciimmunol.adu7961","url":null,"abstract":"<div >Germline-targeting is a promising approach to HIV vaccine development that begins with the elicitation of precursors to broadly neutralizing antibodies (bnAbs), but it remains unclear whether simultaneous elicitation of precursors to multiple epitopes on the HIV envelope (Env) would be inhibited by competition. This study used preclinical mouse models with physiologically relevant frequencies of bnAb precursor–bearing B cells to compare precursor elicitation by coadministration of multiple protein or mRNA lipid nanoparticle (mRNA-LNP) germline-targeting immunogens. These immunogens activate multiple bnAb precursor classes targeting distinct epitopes on Env but with evidence of potential competition. Simultaneous delivery of immunogens encoded by mRNA-LNPs, however, drove maturation across different precursor frequencies and immunogen doses. Furthermore, administration of a cocktail of mRNA-LNP immunogens (N332-GT5 gp151, ApexGT5 gp151, eOD-GT8 60mer, and 10E8-GT12 24mer) led to balanced activation of four distinct bnAb precursor classes, indicating that multiepitope HIV bnAb precursor priming might be successfully implemented in humans but might be immunogen dependent.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adu7961","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310739","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}
Pub Date : 2025-10-17DOI: 10.1126/sciimmunol.adu8878
Henry J. Sutton, Krystal M. Ma, Jon M. Steichen, Torben Schiffner, Tasha K. Altheide, Alessia Liguori, Danny Lu, Michael Kubitz, Erik Georgeson, Nicole Phelps, Ryan Tingle, Nushin B. Alavi, Elana Ben-Akiva, Xiaoya Zhou, Carolyne Kifude, Claudia T. Flynn, Eva Rakasz, Darrell J. Irvine, William R. Schief, Shane Crotty
Inducing broadly neutralizing antibodies (bnAbs) against HIV remains a key challenge in vaccine development. Germline-targeting immunogens have effectively primed bnAb B cell lineages to individual HIV envelope epitopes in humans and nonhuman primates. However, eliciting consistent bnAb breadth requires the induction of multiple bnAb classes. We investigated whether immunization with a combination of germline-targeting immunogens could concurrently prime multiple bnAb lineages in nonhuman primates. Animals were immunized with three immunogens, targeting distinct epitopes: the V3-glycan/N332 supersite, the V2 Apex region, and the membrane-proximal external region (MPER), either individually or in combinations of two or all three. Triple combination immunization transiently reduced V2 Apex and V3-glycan responses, but by 8 weeks postboost, bnAb precursor lineages were observed to all three epitopes. Similar somatic hypermutation was observed across groups, indicative of permissive germinal center responses. These findings support combination germline-targeting immunization as a viable strategy to prime multiple bnAb lineages simultaneously.
{"title":"Simultaneous induction of multiple classes of broadly neutralizing antibody precursors by combination germline-targeting immunization in nonhuman primates","authors":"Henry J. Sutton, Krystal M. Ma, Jon M. Steichen, Torben Schiffner, Tasha K. Altheide, Alessia Liguori, Danny Lu, Michael Kubitz, Erik Georgeson, Nicole Phelps, Ryan Tingle, Nushin B. Alavi, Elana Ben-Akiva, Xiaoya Zhou, Carolyne Kifude, Claudia T. Flynn, Eva Rakasz, Darrell J. Irvine, William R. Schief, Shane Crotty","doi":"10.1126/sciimmunol.adu8878","DOIUrl":"10.1126/sciimmunol.adu8878","url":null,"abstract":"<div >Inducing broadly neutralizing antibodies (bnAbs) against HIV remains a key challenge in vaccine development. Germline-targeting immunogens have effectively primed bnAb B cell lineages to individual HIV envelope epitopes in humans and nonhuman primates. However, eliciting consistent bnAb breadth requires the induction of multiple bnAb classes. We investigated whether immunization with a combination of germline-targeting immunogens could concurrently prime multiple bnAb lineages in nonhuman primates. Animals were immunized with three immunogens, targeting distinct epitopes: the V3-glycan/N332 supersite, the V2 Apex region, and the membrane-proximal external region (MPER), either individually or in combinations of two or all three. Triple combination immunization transiently reduced V2 Apex and V3-glycan responses, but by 8 weeks postboost, bnAb precursor lineages were observed to all three epitopes. Similar somatic hypermutation was observed across groups, indicative of permissive germinal center responses. These findings support combination germline-targeting immunization as a viable strategy to prime multiple bnAb lineages simultaneously.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adu8878","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310738","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}
Pub Date : 2025-10-17DOI: 10.1126/sciimmunol.ado3825
Artem Kalinichenko, Jakob Huemer, Theresa Humer, Matthias Haimel, Michael Svaton, Nicolas Socquet-Juglard, Giovanna Perinetti Casoni, Celine Prakash, Maximilian von der Linde, Julia Pazmandi, Cheryl van de Wetering, Javier Nunez-Fontarnau, Anton Kamnev, Sarah Giuliani, Martin G. Jaeger, Elisa Hahn, Sarah Dobner, Andrea Rukavina, Elise Sylvander, Jacqueline Seigner, Christina Rashkova, Birgit Hoeger, Michael W. Traxlmayr, Manfred Lehner, Yenan T. Bryceson, Janna Saarela, Thomas Hannich, Irinka Castanon, Georg Winter, Loïc Dupré, Kaan Boztug
Regulated exocytosis controls key cellular functions ranging from neurotransmitter release to the secretion of immune mediators, and its disruption is associated with numerous pathologies. The cytotoxic activity of lymphocytes is particularly dependent on regulated and polarized lytic granule delivery toward infected or malignant cells. Although genetic and mechanistic studies have identified factors regulating exocytosis in cytotoxic lymphocytes, a systematic mapping of the relevant factors and their relationships is lacking. Through a genome-scale CRISPR knockout screen in a human natural killer cell line, we characterized a complex genetic network regulating cytotoxic granule exocytosis, with lipid metabolism and protein lipidation among the most prominent pathways. By combining global protein palmitoylation and lipidomic studies, we found that ZDHHC17 drives palmitoylation of the core SNARE complex protein SNAP23 to target cytotoxic granules to GM1-rich lipid rafts whose assembly is controlled by serine palmitoyltransferase. In summary, our study identifies previously unrecognized factors essential for cytotoxic function in human lymphocytes and uncovers how lipid metabolism and protein palmitoylation are involved in the process of regulated exocytosis.
{"title":"Protein palmitoylation and sphingolipid metabolism control regulated exocytosis in cytotoxic lymphocytes","authors":"Artem Kalinichenko, Jakob Huemer, Theresa Humer, Matthias Haimel, Michael Svaton, Nicolas Socquet-Juglard, Giovanna Perinetti Casoni, Celine Prakash, Maximilian von der Linde, Julia Pazmandi, Cheryl van de Wetering, Javier Nunez-Fontarnau, Anton Kamnev, Sarah Giuliani, Martin G. Jaeger, Elisa Hahn, Sarah Dobner, Andrea Rukavina, Elise Sylvander, Jacqueline Seigner, Christina Rashkova, Birgit Hoeger, Michael W. Traxlmayr, Manfred Lehner, Yenan T. Bryceson, Janna Saarela, Thomas Hannich, Irinka Castanon, Georg Winter, Loïc Dupré, Kaan Boztug","doi":"10.1126/sciimmunol.ado3825","DOIUrl":"10.1126/sciimmunol.ado3825","url":null,"abstract":"<div >Regulated exocytosis controls key cellular functions ranging from neurotransmitter release to the secretion of immune mediators, and its disruption is associated with numerous pathologies. The cytotoxic activity of lymphocytes is particularly dependent on regulated and polarized lytic granule delivery toward infected or malignant cells. Although genetic and mechanistic studies have identified factors regulating exocytosis in cytotoxic lymphocytes, a systematic mapping of the relevant factors and their relationships is lacking. Through a genome-scale CRISPR knockout screen in a human natural killer cell line, we characterized a complex genetic network regulating cytotoxic granule exocytosis, with lipid metabolism and protein lipidation among the most prominent pathways. By combining global protein palmitoylation and lipidomic studies, we found that ZDHHC17 drives palmitoylation of the core SNARE complex protein SNAP23 to target cytotoxic granules to GM1-rich lipid rafts whose assembly is controlled by serine palmitoyltransferase. In summary, our study identifies previously unrecognized factors essential for cytotoxic function in human lymphocytes and uncovers how lipid metabolism and protein palmitoylation are involved in the process of regulated exocytosis.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310782","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}
Pub Date : 2025-10-10DOI: 10.1126/sciimmunol.aec5738
{"title":"Erratum for the Research Article “METTL1-mediated m7G methylation of Sarm1 mRNA promotes macrophage inflammatory responses and multiple organ injury” by C. Hou et al.","authors":"","doi":"10.1126/sciimmunol.aec5738","DOIUrl":"10.1126/sciimmunol.aec5738","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145256882","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号