Pub Date : 2025-09-19DOI: 10.1126/sciimmunol.adt5909
Yukako Asano, Claire Y. Ma, Martin M. Limback-Stokin, Adam M. Rochussen, Jane C. Stinchcombe, Gillian M. Griffiths
Target cell recognition by cytotoxic T lymphocytes (CTLs) triggers rapid delivery of cytolytic granules to the immune synapse directed by the centrosome. Recent studies have also identified a rapid burst of T cell receptor (TCR)–activated transcription that contributes to CTL-mediated killing. To determine how de novo transcription might be coordinated with intracellular polarization, we asked when transcription factor translocation to the nucleus occurs relative to TCR activation and centrosome polarization within individual CTLs. Upon target cell recognition, the nucleus polarized to and contacted the immune synapse, preceding centrosome docking. The nucleus distorted as it moved, with transcription factors NFAT and NF-κB accumulating in the nucleus during polarization. Inhibition or deletion of myosin IIA prevented both nuclear polarization and transcription factor translocation. Thus, nuclear polarization facilitates an early transcriptional burst that occurs as CTLs encounter targets and the consequent delivery of newly synthesized cytokines to the immune synapse.
{"title":"Nuclear polarization to the immune synapse facilitates an early transcriptional burst","authors":"Yukako Asano, Claire Y. Ma, Martin M. Limback-Stokin, Adam M. Rochussen, Jane C. Stinchcombe, Gillian M. Griffiths","doi":"10.1126/sciimmunol.adt5909","DOIUrl":"10.1126/sciimmunol.adt5909","url":null,"abstract":"<div >Target cell recognition by cytotoxic T lymphocytes (CTLs) triggers rapid delivery of cytolytic granules to the immune synapse directed by the centrosome. Recent studies have also identified a rapid burst of T cell receptor (TCR)–activated transcription that contributes to CTL-mediated killing. To determine how de novo transcription might be coordinated with intracellular polarization, we asked when transcription factor translocation to the nucleus occurs relative to TCR activation and centrosome polarization within individual CTLs. Upon target cell recognition, the nucleus polarized to and contacted the immune synapse, preceding centrosome docking. The nucleus distorted as it moved, with transcription factors NFAT and NF-κB accumulating in the nucleus during polarization. Inhibition or deletion of myosin IIA prevented both nuclear polarization and transcription factor translocation. Thus, nuclear polarization facilitates an early transcriptional burst that occurs as CTLs encounter targets and the consequent delivery of newly synthesized cytokines to the immune synapse.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088988","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 : 2025-09-12DOI: 10.1126/sciimmunol.adq8970
Xin Zhao, Shengen Shawn Hu, Wen-Han Lee, Johannes L. Zakrzewski, Qing-Sheng Mi, Rachel K. Rosenstein, Chongzhi Zang, Xiaoke Ma, Hai-Hui Xue
Bone marrow–derived multipotent hematopoietic progenitors seed the thymus and generate early thymic progenitors (ETPs). However, the factors governing ETP formation remain poorly defined. Using single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), we dissected the heterogeneity of transcriptomic and chromatin accessibility landscapes in murine ETPs. Whereas Tcf1− ETPs exhibited higher proliferative capacity, Tcf1+ ETPs appeared to be immediate, more robust precursors to T lineage–specified early thymocytes. Prethymic ablation of Tcf1 and its homolog Lef1 severely impaired ETP formation in vivo. Whereas ablating Tcf1 alone had limited impact, loss of both Tcf1 and Lef1 impaired transcriptional activation of Notch1 and Notch pathway effector molecules, including Hes1 and Hhex, accompanied by aberrantly induced B cell and myeloid gene programs. Acute deletion of both factors compromised Notch pathway, glycolysis, and T cell gene programs in emergent ETPs ex vivo. Thus, Tcf1 and Lef1 act upstream of the Notch pathway, functioning as prethymic initiators of ETP fate and intrathymic gatekeepers of ETP identity and T lineage potential.
{"title":"Single-cell multiomics identifies Tcf1 and Lef1 as key initiators of early thymic progenitor fate","authors":"Xin Zhao, Shengen Shawn Hu, Wen-Han Lee, Johannes L. Zakrzewski, Qing-Sheng Mi, Rachel K. Rosenstein, Chongzhi Zang, Xiaoke Ma, Hai-Hui Xue","doi":"10.1126/sciimmunol.adq8970","DOIUrl":"10.1126/sciimmunol.adq8970","url":null,"abstract":"<div >Bone marrow–derived multipotent hematopoietic progenitors seed the thymus and generate early thymic progenitors (ETPs). However, the factors governing ETP formation remain poorly defined. Using single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), we dissected the heterogeneity of transcriptomic and chromatin accessibility landscapes in murine ETPs. Whereas Tcf1<sup>−</sup> ETPs exhibited higher proliferative capacity, Tcf1<sup>+</sup> ETPs appeared to be immediate, more robust precursors to T lineage–specified early thymocytes. Prethymic ablation of Tcf1 and its homolog Lef1 severely impaired ETP formation in vivo. Whereas ablating Tcf1 alone had limited impact, loss of both Tcf1 and Lef1 impaired transcriptional activation of <i>Notch1</i> and Notch pathway effector molecules, including <i>Hes1</i> and <i>Hhex</i>, accompanied by aberrantly induced B cell and myeloid gene programs. Acute deletion of both factors compromised Notch pathway, glycolysis, and T cell gene programs in emergent ETPs ex vivo. Thus, Tcf1 and Lef1 act upstream of the Notch pathway, functioning as prethymic initiators of ETP fate and intrathymic gatekeepers of ETP identity and T lineage potential.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043473","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}
RNA modifications regulate phenotype and function of macrophages by regulating RNA translation, splicing, and stability. However, the role of N7-methylguanosine (m7G) modification in macrophages and inflammation remains unexplored. In this study, we observed elevated levels of the methyltransferase METTL1 and m7G modifications in macrophages from mouse and human tissues during acute kidney injury (AKI). METTL1 deficiency in myeloid cells mitigated multiorgan inflammation induced by cecal ligation and puncture and renal ischemia/reperfusion. Genetic deletion of METTL1 inhibited macrophage proinflammatory responses. We identified internal Sarm1 messenger RNA (mRNA) as a target of m7G modification that controls macrophage metabolic reprogramming. METTL1 deficiency in macrophages inhibited metabolic reprogramming, which was reversed by SARM1 overexpression that induced NAD+ decline. Pharmacologically, SA91-0178, a specific METTL1 inhibitor, effectively alleviated tissue injury during septic inflammation. Collectively, our findings suggest that m7G modification enhances the stability of Sarm1 mRNA, thereby resulting in NAD+ imbalance in macrophages, indicating that METTL1 may serve as a potential therapeutic target for systemic inflammation.
{"title":"METTL1-mediated m7G methylation of Sarm1 mRNA promotes macrophage inflammatory responses and multiple organ injury","authors":"Chao Hou, Xin-ru Zhang, Jie Wei, Jia-nan Wang, Jian Gao, Zhi-juan Wang, Shuai-shuai Xie, Tong Chen, Tao Sun, Tian Pu, Ju-tao Yu, Xiao-guo Suo, Zi-ye Mei, Fan-rong Zhang, Juan Jin, Wen-man Zhao, Yu-xian Shen, Xiao-ming Meng","doi":"10.1126/sciimmunol.adv4810","DOIUrl":"10.1126/sciimmunol.adv4810","url":null,"abstract":"<div >RNA modifications regulate phenotype and function of macrophages by regulating RNA translation, splicing, and stability. However, the role of <i>N</i><sup>7</sup>-methylguanosine (m<sup>7</sup>G) modification in macrophages and inflammation remains unexplored. In this study, we observed elevated levels of the methyltransferase METTL1 and m<sup>7</sup>G modifications in macrophages from mouse and human tissues during acute kidney injury (AKI). METTL1 deficiency in myeloid cells mitigated multiorgan inflammation induced by cecal ligation and puncture and renal ischemia/reperfusion. Genetic deletion of METTL1 inhibited macrophage proinflammatory responses. We identified internal <i>Sarm1</i> messenger RNA (mRNA) as a target of m<sup>7</sup>G modification that controls macrophage metabolic reprogramming. METTL1 deficiency in macrophages inhibited metabolic reprogramming, which was reversed by SARM1 overexpression that induced NAD<sup>+</sup> decline. Pharmacologically, SA91-0178, a specific METTL1 inhibitor, effectively alleviated tissue injury during septic inflammation. Collectively, our findings suggest that m<sup>7</sup>G modification enhances the stability of <i>Sarm1</i> mRNA, thereby resulting in NAD<sup>+</sup> imbalance in macrophages, indicating that METTL1 may serve as a potential therapeutic target for systemic inflammation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adv4810","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999172","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 : 2025-09-05DOI: 10.1126/sciimmunol.adz6869
Alejandra Mendoza, Regina Bou-Puerto, Juan Sebastian Jara, Stanislav Dikiy, Paolo Giovanelli, Danilo Correa, Susanna Manenti, Emma S. Andretta, Chitra L. Dahia, Alexander Y. Rudensky
The skin integrates diverse signals discerned by sensory neurons and immune cells to elicit adaptive responses to a range of stresses. Considering interactions between nervous and immune systems, we examined whether regulatory T (Treg) cells, which suppress systemic and local inflammation, can modulate activation of peripheral neurons. Acute Treg cell “loss of function” increased neuronal activation to noxious stimuli independently of their immunosuppressive function. This activity was mediated by a Treg cell subset capable of production of enkephalins encoded by the gene Penk, whose expression is facilitated by combined TCR and glucocorticoid receptor signaling. Punctual selective depletion of Penk-expressing Treg cells or specific ablation of Penk in Treg cells increased neuronal activation in response to noxious stimuli and associated inflammation. Our study indicates that a population of tissular Treg cells exhibits neuromodulatory activity to restrain local inflammation in the skin.
{"title":"Enkephalin-producing regulatory T cells in the skin restrain local inflammation through control of nociception","authors":"Alejandra Mendoza, Regina Bou-Puerto, Juan Sebastian Jara, Stanislav Dikiy, Paolo Giovanelli, Danilo Correa, Susanna Manenti, Emma S. Andretta, Chitra L. Dahia, Alexander Y. Rudensky","doi":"10.1126/sciimmunol.adz6869","DOIUrl":"10.1126/sciimmunol.adz6869","url":null,"abstract":"<div >The skin integrates diverse signals discerned by sensory neurons and immune cells to elicit adaptive responses to a range of stresses. Considering interactions between nervous and immune systems, we examined whether regulatory T (T<sub>reg</sub>) cells, which suppress systemic and local inflammation, can modulate activation of peripheral neurons. Acute T<sub>reg</sub> cell “loss of function” increased neuronal activation to noxious stimuli independently of their immunosuppressive function. This activity was mediated by a T<sub>reg</sub> cell subset capable of production of enkephalins encoded by the gene <i>Penk</i>, whose expression is facilitated by combined TCR and glucocorticoid receptor signaling. Punctual selective depletion of <i>Penk</i>-expressing T<sub>reg</sub> cells or specific ablation of <i>Penk</i> in T<sub>reg</sub> cells increased neuronal activation in response to noxious stimuli and associated inflammation. Our study indicates that a population of tissular T<sub>reg</sub> cells exhibits neuromodulatory activity to restrain local inflammation in the skin.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adz6869","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999188","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 : 2025-09-05DOI: 10.1126/sciimmunol.aeb8328
Cait A. McAlindon, Rachael A. Clark
A new orally bioavailable HO-1 inhibitor enhances tumor clearance after chemotherapy in mice by enhancing the recruitment of CD8 T cells.
一种新的口服生物可利用的HO-1抑制剂通过增强CD8 T细胞的募集来增强小鼠化疗后的肿瘤清除。
{"title":"It’s getting hot in here: Heating up the tumor microenvironment with an oral HO-1 inhibitor","authors":"Cait A. McAlindon, Rachael A. Clark","doi":"10.1126/sciimmunol.aeb8328","DOIUrl":"10.1126/sciimmunol.aeb8328","url":null,"abstract":"<div >A new orally bioavailable HO-1 inhibitor enhances tumor clearance after chemotherapy in mice by enhancing the recruitment of CD8 T cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999159","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 : 2025-09-05DOI: 10.1126/sciimmunol.aeb8333
Ana C. Anderson, Manu Rangachari
Loss-of-function mutations in NOD2 may predict positive response to PD-1 blockade monotherapy in cancer.
NOD2的功能缺失突变可能预测癌症患者对PD-1阻断单药治疗的阳性反应。
{"title":"Loss-of-function mutations ensure that response to immune checkpoint therapy is NOD2 be denied","authors":"Ana C. Anderson, Manu Rangachari","doi":"10.1126/sciimmunol.aeb8333","DOIUrl":"10.1126/sciimmunol.aeb8333","url":null,"abstract":"<div >Loss-of-function mutations in NOD2 may predict positive response to PD-1 blockade monotherapy in cancer.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999178","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 : 2025-09-05DOI: 10.1126/sciimmunol.adq0457
Mengyue Wu, Kepan Linghu, Qimin Yin, Ping He, Xinyang Yu, Peng Hu, Rongying He, Qinyun Du, Shengli Wang, Xi Chen, Shaohui Wang, Xingyun Wu, Mingfu Zhang, Keren Peng, Xiang Wang, Juxiu Liu, Dong Deng, Guangchao Cao, Kui Wang, Xianli Meng, Quanli Yang, Dezhi Mu, Zhinan Yin, Lu Chen, Jiyu Tong
Naïve T cells are maintained in a homeostatic state to preserve a stable T cell pool with diverse T cell receptor (TCR) repertoires, ensuring preparedness for priming. However, the underlying mechanisms controlling naïve T cell homeostasis and priming remain unclear. Leveraging a machine learning–based functional genetic screen, we identified DEAD-box helicase 55 (Ddx55) as the top factor responsible for naïve T cell homeostasis. DDX55 was highly expressed in naïve T cells and suppressed enhancer- and promoter-like transposable elements (TEs) near T cell activation–associated genes. Ddx55 loss led to derepression of these TEs, resulting in TE-derived R loops and genomic instability, ultimately disrupting naïve T cell homeostasis and abolishing T cell proliferation. Mechanistically, DDX55-targeted TEs harbored myelocytomatosis oncogene (MYC)–binding motifs. DDX55 directly bound MYC and restricted its access to these TE loci, thereby preventing inappropriate TE activation in naïve T cells. Thus, naïve T cells exploit DDX55 as a vital regulator of T cell activation, ensuring their genomic stability and homeostatic maintenance.
{"title":"DDX55 safeguards naïve T cell homeostasis by suppressing activation-promoting transposable elements","authors":"Mengyue Wu, Kepan Linghu, Qimin Yin, Ping He, Xinyang Yu, Peng Hu, Rongying He, Qinyun Du, Shengli Wang, Xi Chen, Shaohui Wang, Xingyun Wu, Mingfu Zhang, Keren Peng, Xiang Wang, Juxiu Liu, Dong Deng, Guangchao Cao, Kui Wang, Xianli Meng, Quanli Yang, Dezhi Mu, Zhinan Yin, Lu Chen, Jiyu Tong","doi":"10.1126/sciimmunol.adq0457","DOIUrl":"10.1126/sciimmunol.adq0457","url":null,"abstract":"<div >Naïve T cells are maintained in a homeostatic state to preserve a stable T cell pool with diverse T cell receptor (TCR) repertoires, ensuring preparedness for priming. However, the underlying mechanisms controlling naïve T cell homeostasis and priming remain unclear. Leveraging a machine learning–based functional genetic screen, we identified <i>DEAD-box helicase 55</i> (<i>Ddx55</i>) as the top factor responsible for naïve T cell homeostasis. DDX55 was highly expressed in naïve T cells and suppressed enhancer- and promoter-like transposable elements (TEs) near T cell activation–associated genes. <i>Ddx55</i> loss led to derepression of these TEs, resulting in TE-derived R loops and genomic instability, ultimately disrupting naïve T cell homeostasis and abolishing T cell proliferation. Mechanistically, DDX55-targeted TEs harbored myelocytomatosis oncogene (MYC)–binding motifs. DDX55 directly bound MYC and restricted its access to these TE loci, thereby preventing inappropriate TE activation in naïve T cells. Thus, naïve T cells exploit DDX55 as a vital regulator of T cell activation, ensuring their genomic stability and homeostatic maintenance.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999186","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 : 2025-08-29DOI: 10.1126/sciimmunol.adu4610
Sam M. Murray, Ali Amini, Helen Ferry, Lucy C. Garner, Maria Fransiska Pudjohartono, Barbara Kronsteiner, Sagida Bibi, Andrew J. Pollard, Eleanor Barnes, Teresa Lambe, Susanna Dunachie, Paul Klenerman, Nicholas M. Provine
Functional T cell responses are crucial for protective immunity induced by COVID-19 vaccination, but factors influencing the quality of these responses are incompletely understood. We used an activation-induced marker (AIM) assay and single-cell transcriptomic sequencing to analyze SARS-CoV-2 spike-responsive T cells after mild SARS-CoV-2 infection or after one or two doses of mRNA–lipid nanoparticle (mRNA-LNP) or adenoviral-vectored COVID-19 vaccines. Our findings revealed broad functional and clonal heterogeneity in T cells generated by vaccination or infection, including multiple distinct effector populations. T cell function was largely conserved between COVID-19 vaccine platforms but was distinct compared with SARS-CoV-2 infection. Notably, the dosing interval greatly influenced the quality of T cells after two vaccine doses, particularly after mRNA-LNP vaccination, where a longer interval led to reduced inflammatory signaling and increased secondary proliferation. These insights enhance our understanding of SARS-CoV-2–specific T cells and inform the optimization of mRNA vaccination regimens.
{"title":"Dosing interval is a major factor determining the quality of T cells induced by SARS-CoV-2 mRNA and adenoviral vector vaccines","authors":"Sam M. Murray, Ali Amini, Helen Ferry, Lucy C. Garner, Maria Fransiska Pudjohartono, Barbara Kronsteiner, Sagida Bibi, Andrew J. Pollard, Eleanor Barnes, Teresa Lambe, Susanna Dunachie, Paul Klenerman, Nicholas M. Provine","doi":"10.1126/sciimmunol.adu4610","DOIUrl":"10.1126/sciimmunol.adu4610","url":null,"abstract":"<div >Functional T cell responses are crucial for protective immunity induced by COVID-19 vaccination, but factors influencing the quality of these responses are incompletely understood. We used an activation-induced marker (AIM) assay and single-cell transcriptomic sequencing to analyze SARS-CoV-2 spike-responsive T cells after mild SARS-CoV-2 infection or after one or two doses of mRNA–lipid nanoparticle (mRNA-LNP) or adenoviral-vectored COVID-19 vaccines. Our findings revealed broad functional and clonal heterogeneity in T cells generated by vaccination or infection, including multiple distinct effector populations. T cell function was largely conserved between COVID-19 vaccine platforms but was distinct compared with SARS-CoV-2 infection. Notably, the dosing interval greatly influenced the quality of T cells after two vaccine doses, particularly after mRNA-LNP vaccination, where a longer interval led to reduced inflammatory signaling and increased secondary proliferation. These insights enhance our understanding of SARS-CoV-2–specific T cells and inform the optimization of mRNA vaccination regimens.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adu4610","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915926","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 : 2025-08-29DOI: 10.1126/sciimmunol.adu3337
Ali Amini, Lucy C. Garner, Robert H. Shaw, Neil Wrigley Kelly, Sandra Adele, Donal T. Skelly, Wanwisa Dejnirattisai, Melanie Greenland, Xinxue Liu, Amelia Heslington, Carl-Philipp Hackstein, Sam M. Murray, Cristina Riquelme Vano, Lizzie Stafford, Sile Johnson, Katia Sayaf, Maria Fransiska Pudjohartono, Elizabeth A. Clutterbuck, PITCH Consortium‡, Com-COV Study Group‡, Sagida Bibi, Christopher P. Conlon, Tim James, Katie Jeffery, Barbara Kronsteiner, Alexander J. Mentzer, Donal O’Shea, Maheshi N. Ramasamy, Gavin R. Screaton, Matthew D. Snape, Andrew E. Hogan, Eleanor Barnes, Teresa Lambe, Susanna J. Dunachie, Nicholas M. Provine, Paul Klenerman
Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes—mucosal-associated invariant T (MAIT) cells and Vδ2+ γδ T cells—which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)–mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell–derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ–licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.
{"title":"MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines","authors":"Ali Amini, Lucy C. Garner, Robert H. Shaw, Neil Wrigley Kelly, Sandra Adele, Donal T. Skelly, Wanwisa Dejnirattisai, Melanie Greenland, Xinxue Liu, Amelia Heslington, Carl-Philipp Hackstein, Sam M. Murray, Cristina Riquelme Vano, Lizzie Stafford, Sile Johnson, Katia Sayaf, Maria Fransiska Pudjohartono, Elizabeth A. Clutterbuck, PITCH Consortium‡, Com-COV Study Group‡, Sagida Bibi, Christopher P. Conlon, Tim James, Katie Jeffery, Barbara Kronsteiner, Alexander J. Mentzer, Donal O’Shea, Maheshi N. Ramasamy, Gavin R. Screaton, Matthew D. Snape, Andrew E. Hogan, Eleanor Barnes, Teresa Lambe, Susanna J. Dunachie, Nicholas M. Provine, Paul Klenerman","doi":"10.1126/sciimmunol.adu3337","DOIUrl":"10.1126/sciimmunol.adu3337","url":null,"abstract":"<div >Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes—mucosal-associated invariant T (MAIT) cells and Vδ2<sup>+</sup> γδ T cells—which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)–mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell–derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ–licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adu3337","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144918904","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 : 2025-08-22DOI: 10.1126/sciimmunol.adt6660
Krystal M. Ma, Henry J. Sutton, Payal P. Pratap, Jon M. Steichen, Diane Carnathan, James Quinn, Oleksandr Kalyuzhniy, Alessia Liguori, Sashank Agrawal, Sabyasachi Baboo, Patrick Madden, Christopher A. Cottrell, Jordan R. Willis, Jeong-Hyun Lee, Elise Landais, Xiaozhen Hu, Parham Ramezani-Rad, Gabriel Ozorowski, Vanessa R. Lewis, Jolene K. Diedrich, Xiaoya Zhou, Tasha K. Altheide, Nicole Phelps, Erik Georgeson, Nushin B. Alavi, Danny Lu, Saman Eskandarzadeh, Michael Kubitz, Yumiko Adachi, Tina-Marie Mullen, Murillo Silva, Mariane B. Melo, Sunny Himansu, Darrell J. Irvine, Dennis R. Burton, John R. Yates III, James C. Paulson, Devin Sok, Ian A. Wilson, Guido Silvestri, Andrew B. Ward, Shane Crotty, William R. Schief
An effective prophylactic HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). bnAbs to the Apex region of the HIV envelope glycoprotein (Env) are promising targets for vaccination because of their relatively low somatic hypermutation compared with other bnAbs. Most Apex bnAbs engage Env using an exceptionally long heavy-chain complementarity-determining region 3 (HCDR3) containing specific binding motifs, which reduces bnAb precursor frequency and makes priming of rare bnAb precursors a likely limiting step in the path to Apex bnAb induction. We found that adjuvanted protein or mRNA lipid nanoparticle (LNP) immunization of rhesus macaques with ApexGT6, an Env trimer engineered to bind Apex bnAb precursors, consistently induced Apex bnAb–related precursors with long HCDR3s bearing bnAb-like sequence motifs. Cryo–electron microscopy revealed that elicited Apex bnAb–related HCDR3s had structures combining elements of several prototype Apex bnAbs. These results achieve a critical HIV vaccine development milestone in outbred primates.
{"title":"HIV broadly neutralizing antibody precursors to the Apex epitope induced in nonhuman primates","authors":"Krystal M. Ma, Henry J. Sutton, Payal P. Pratap, Jon M. Steichen, Diane Carnathan, James Quinn, Oleksandr Kalyuzhniy, Alessia Liguori, Sashank Agrawal, Sabyasachi Baboo, Patrick Madden, Christopher A. Cottrell, Jordan R. Willis, Jeong-Hyun Lee, Elise Landais, Xiaozhen Hu, Parham Ramezani-Rad, Gabriel Ozorowski, Vanessa R. Lewis, Jolene K. Diedrich, Xiaoya Zhou, Tasha K. Altheide, Nicole Phelps, Erik Georgeson, Nushin B. Alavi, Danny Lu, Saman Eskandarzadeh, Michael Kubitz, Yumiko Adachi, Tina-Marie Mullen, Murillo Silva, Mariane B. Melo, Sunny Himansu, Darrell J. Irvine, Dennis R. Burton, John R. Yates III, James C. Paulson, Devin Sok, Ian A. Wilson, Guido Silvestri, Andrew B. Ward, Shane Crotty, William R. Schief","doi":"10.1126/sciimmunol.adt6660","DOIUrl":"10.1126/sciimmunol.adt6660","url":null,"abstract":"<div >An effective prophylactic HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). bnAbs to the Apex region of the HIV envelope glycoprotein (Env) are promising targets for vaccination because of their relatively low somatic hypermutation compared with other bnAbs. Most Apex bnAbs engage Env using an exceptionally long heavy-chain complementarity-determining region 3 (HCDR3) containing specific binding motifs, which reduces bnAb precursor frequency and makes priming of rare bnAb precursors a likely limiting step in the path to Apex bnAb induction. We found that adjuvanted protein or mRNA lipid nanoparticle (LNP) immunization of rhesus macaques with ApexGT6, an Env trimer engineered to bind Apex bnAb precursors, consistently induced Apex bnAb–related precursors with long HCDR3s bearing bnAb-like sequence motifs. Cryo–electron microscopy revealed that elicited Apex bnAb–related HCDR3s had structures combining elements of several prototype Apex bnAbs. These results achieve a critical HIV vaccine development milestone in outbred primates.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adt6660","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144891754","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}
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