Pub Date : 2025-01-24DOI: 10.1126/sciimmunol.ado9572
Jared Feldman, Ana Sofia Ferreira Ramos, Mya Vu, Daniel P. Maurer, Victoria C. Rosado, Daniel Lingwood, Goran Bajic, Aaron G. Schmidt
Understanding the naïve B cell repertoire and its specificity for potential zoonotic threats, such as the highly pathogenic avian influenza (HPAI) H5Nx viruses, may allow prediction of infection- or vaccine-specific responses. However, this naïve repertoire and the possibility to respond to emerging, prepandemic viruses are largely undetermined. Here, we profiled naïve B cell reactivity against a prototypical HPAI H5 hemagglutinin (HA), the major target of antibody responses. We found that the frequency of H5-specific human naïve B cells targeting the HA “head” domain was increased relative to cross-reactive B cells to a circulating seasonal H1N1 strain. We classified the isolated monoclonal antibodies (mAbs) by the HA epitopes engaged and found that selected mAbs neutralized H5N1 at germline. We determined a cryo–electron microscopic structure of one mAb in complex with H5 HA to define its epitope. Our study defines the naïve human B cell repertoire recognizing a potentially zoonotic HPAI.
{"title":"Human naïve B cells recognize prepandemic influenza virus hemagglutinins","authors":"Jared Feldman, Ana Sofia Ferreira Ramos, Mya Vu, Daniel P. Maurer, Victoria C. Rosado, Daniel Lingwood, Goran Bajic, Aaron G. Schmidt","doi":"10.1126/sciimmunol.ado9572","DOIUrl":"10.1126/sciimmunol.ado9572","url":null,"abstract":"<div >Understanding the naïve B cell repertoire and its specificity for potential zoonotic threats, such as the highly pathogenic avian influenza (HPAI) H5Nx viruses, may allow prediction of infection- or vaccine-specific responses. However, this naïve repertoire and the possibility to respond to emerging, prepandemic viruses are largely undetermined. Here, we profiled naïve B cell reactivity against a prototypical HPAI H5 hemagglutinin (HA), the major target of antibody responses. We found that the frequency of H5-specific human naïve B cells targeting the HA “head” domain was increased relative to cross-reactive B cells to a circulating seasonal H1N1 strain. We classified the isolated monoclonal antibodies (mAbs) by the HA epitopes engaged and found that selected mAbs neutralized H5N1 at germline. We determined a cryo–electron microscopic structure of one mAb in complex with H5 HA to define its epitope. Our study defines the naïve human B cell repertoire recognizing a potentially zoonotic HPAI.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ado9572","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030939","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 : 2025-01-17DOI: 10.1126/sciimmunol.adp5218
Sharidan Brown, Aleksandar Antanasijevic, Leigh M. Sewall, Daniel Montiel Garcia, Philip J. M. Brouwer, Rogier W. Sanders, Andrew B. Ward
Vaccination strategies against HIV-1 aim to elicit broadly neutralizing antibodies (bnAbs) using prime-boost regimens with HIV envelope (Env) immunogens. Epitope mapping has shown that early antibody responses are directed to easily accessible nonneutralizing epitopes on Env instead of bnAb epitopes. Autologously neutralizing antibody responses appear upon boosting, once immunodominant epitopes are saturated. Here, we use electron microscopy–based polyclonal epitope mapping (EMPEM) to elucidate how repeated immunization with HIV Env SOSIP immunogens results in the generation of Ab2α anti-idiotypic antibodies in rabbits and rhesus macaques. We present the structures of six anti–immune complex antibodies and find that they target idiotopes composed of framework regions of antibodies bound to Env. Examination of cryo–electron microscopy density enabled prediction of sequences for an anti–immune complex antibody, the paratope of which is enriched with aromatic amino acids. This work sheds light on current vaccine development efforts for HIV, as well as for other pathogens in which repeated exposure to antigen is required.
{"title":"Anti–immune complex antibodies are elicited during repeated immunization with HIV Env immunogens","authors":"Sharidan Brown, Aleksandar Antanasijevic, Leigh M. Sewall, Daniel Montiel Garcia, Philip J. M. Brouwer, Rogier W. Sanders, Andrew B. Ward","doi":"10.1126/sciimmunol.adp5218","DOIUrl":"10.1126/sciimmunol.adp5218","url":null,"abstract":"<div >Vaccination strategies against HIV-1 aim to elicit broadly neutralizing antibodies (bnAbs) using prime-boost regimens with HIV envelope (Env) immunogens. Epitope mapping has shown that early antibody responses are directed to easily accessible nonneutralizing epitopes on Env instead of bnAb epitopes. Autologously neutralizing antibody responses appear upon boosting, once immunodominant epitopes are saturated. Here, we use electron microscopy–based polyclonal epitope mapping (EMPEM) to elucidate how repeated immunization with HIV Env SOSIP immunogens results in the generation of Ab2α anti-idiotypic antibodies in rabbits and rhesus macaques. We present the structures of six anti–immune complex antibodies and find that they target idiotopes composed of framework regions of antibodies bound to Env. Examination of cryo–electron microscopy density enabled prediction of sequences for an anti–immune complex antibody, the paratope of which is enriched with aromatic amino acids. This work sheds light on current vaccine development efforts for HIV, as well as for other pathogens in which repeated exposure to antigen is required.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp5218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987476","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 : 2025-01-17DOI: 10.1126/sciimmunol.adf4726
Vidit Bhandarkar, Teresa Dinter, Stefani Spranger
Immune responses against cancer are dominated by T cell exhaustion and dysfunction. Recent advances have underscored the critical role of early priming interactions in establishing T cell fates. In this review, we explore the importance of dendritic cell (DC) signals in specifying CD8+ T cell fates in cancer, drawing on insights from acute and chronic viral infection models. We highlight the role of DCs in lymph nodes and tumors in maintaining stem-like CD8+ T cells, which are critical for durable antitumor immune responses. Understanding how CD8+ T cell fates are determined will enable the rational design of immunotherapies, particularly therapeutic cancer vaccines, that can modulate DC–T cell interactions to generate beneficial CD8+ T cell fates.
{"title":"Architects of immunity: How dendritic cells shape CD8+ T cell fate in cancer","authors":"Vidit Bhandarkar, Teresa Dinter, Stefani Spranger","doi":"10.1126/sciimmunol.adf4726","DOIUrl":"10.1126/sciimmunol.adf4726","url":null,"abstract":"<div >Immune responses against cancer are dominated by T cell exhaustion and dysfunction. Recent advances have underscored the critical role of early priming interactions in establishing T cell fates. In this review, we explore the importance of dendritic cell (DC) signals in specifying CD8<sup>+</sup> T cell fates in cancer, drawing on insights from acute and chronic viral infection models. We highlight the role of DCs in lymph nodes and tumors in maintaining stem-like CD8<sup>+</sup> T cells, which are critical for durable antitumor immune responses. Understanding how CD8<sup>+</sup> T cell fates are determined will enable the rational design of immunotherapies, particularly therapeutic cancer vaccines, that can modulate DC–T cell interactions to generate beneficial CD8<sup>+</sup> T cell fates.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987475","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 : 2025-01-10DOI: 10.1126/sciimmunol.adl4909
Cody Elkins, Chengyu Ye, Pulavendran Sivasami, Roy Mulpur, Pamela P. Diaz-Saldana, Amy Peng, Miaoer Xu, Yeun-po Chiang, Samara Moll, Dormarie E. Rivera-Rodriguez, Luisa Cervantes-Barragan, Tuoqi Wu, Byron B. Au-Yeung, Christopher D. Scharer, Mandy L. Ford, Haydn Kissick, Chaoran Li
Regulatory T cells (Tregs) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT Tregs under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2hi VAT Treg subsets. Treg-specific deletion of Srebf2, the master regulator of cholesterol homeostasis, selectively reduced ST2hi VAT Tregs, increasing VAT inflammation and insulin resistance. Single-cell RNA/T cell receptor (TCR) sequencing revealed a specific loss and reduced clonal expansion of ST2hi VAT Treg subsets after Srebf2 deletion. Srebf2-mediated cholesterol homeostasis potentiated strong TCR signaling, which preferentially promoted ST2hi VAT Treg accumulation. However, long-term high-fat diet feeding disrupted VAT Treg cholesterol homeostasis and impaired clonal expansion of the ST2hi subset. Restoring Treg cholesterol homeostasis rescued VAT Treg accumulation in obese mice, suggesting that modulation of cholesterol homeostasis could be a promising strategy for Treg-targeted therapies in obesity-associated metabolic diseases.
调节性T细胞（T regs）在内脏脂肪组织（VAT）中积累以维持全身代谢稳态，但在肥胖期间下降。在此，我们探讨了在正常和高脂饲料喂养条件下控制VAT T regs稳态、组成和功能的代谢途径。我们发现胆固醇代谢在ST2 hi VAT T reg亚群中特异性上调。Srebf2（胆固醇稳态的主要调节因子）的T regs特异性缺失，选择性地降低了ST2 hi VAT T regs，增加了VAT炎症和胰岛素抵抗。单细胞RNA/T细胞受体（TCR）测序显示，Srebf2缺失后，ST2 hi VAT T reg亚群的特异性缺失和克隆扩增减少。Srebf2介导的胆固醇稳态增强了强烈的TCR信号，这优先促进了ST2 hi VAT T reg的积累。然而，长期的高脂肪饮食喂养破坏了VAT T reg胆固醇的稳态，并损害了ST2 hi亚群的克隆扩增。恢复T - reg胆固醇稳态可以挽救肥胖小鼠的VAT T - reg积累，这表明调节胆固醇稳态可能是一种有前途的T - reg靶向治疗肥胖相关代谢疾病的策略。
{"title":"Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis","authors":"Cody Elkins, Chengyu Ye, Pulavendran Sivasami, Roy Mulpur, Pamela P. Diaz-Saldana, Amy Peng, Miaoer Xu, Yeun-po Chiang, Samara Moll, Dormarie E. Rivera-Rodriguez, Luisa Cervantes-Barragan, Tuoqi Wu, Byron B. Au-Yeung, Christopher D. Scharer, Mandy L. Ford, Haydn Kissick, Chaoran Li","doi":"10.1126/sciimmunol.adl4909","DOIUrl":"10.1126/sciimmunol.adl4909","url":null,"abstract":"<div >Regulatory T cells (T<sub>regs</sub>) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT T<sub>regs</sub> under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2<sup>hi</sup> VAT T<sub>reg</sub> subsets. T<sub>reg</sub>-specific deletion of <i>Srebf2</i>, the master regulator of cholesterol homeostasis, selectively reduced ST2<sup>hi</sup> VAT T<sub>regs</sub>, increasing VAT inflammation and insulin resistance. Single-cell RNA/T cell receptor (TCR) sequencing revealed a specific loss and reduced clonal expansion of ST2<sup>hi</sup> VAT T<sub>reg</sub> subsets after <i>Srebf2</i> deletion. <i>Srebf2</i>-mediated cholesterol homeostasis potentiated strong TCR signaling, which preferentially promoted ST2<sup>hi</sup> VAT T<sub>reg</sub> accumulation. However, long-term high-fat diet feeding disrupted VAT T<sub>reg</sub> cholesterol homeostasis and impaired clonal expansion of the ST2<sup>hi</sup> subset. Restoring T<sub>reg</sub> cholesterol homeostasis rescued VAT T<sub>reg</sub> accumulation in obese mice, suggesting that modulation of cholesterol homeostasis could be a promising strategy for T<sub>reg</sub>-targeted therapies in obesity-associated metabolic diseases.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939926","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 : 2025-01-10DOI: 10.1126/sciimmunol.adk0073
Rama K. Gurram, Peng Li, Jangsuk Oh, Xi Chen, Rosanne Spolski, Xianglan Yao, Jian-Xin Lin, Suyasha Roy, Matthew J. Liao, Chengyu Liu, Zu-Xi Yu, Stewart J. Levine, Jinfang Zhu, Warren J. Leonard
Thymic stromal lymphopoietin (TSLP) is a type I cytokine that promotes allergic responses and mediates type 2 immunity. A balance between effector T cells (Teffs), which drive the immune response, and regulatory T cells (Tregs), which suppress the response, is required for proper immune homeostasis. Here, we report that TSLP differentially acts on Teffs versus Tregs to balance type 2 immunity. As expected, deletion of TSLP receptor (TSLPR) on all T cells (Cd4CreCrlf2fl/fl mice) resulted in lower numbers of T helper 2 (TH2) cells and diminished ovalbumin-induced airway inflammation, but selective deletion of TSLPR on Tregs (Foxp3YFP-Cre/YCrlf2fl/fl mice) resulted in increased interleukin-5 (IL-5)– and IL-13–secreting TH2 cells and lung eosinophilia. Moreover, TSLP augmented the expression of factors that stabilize Tregs. During type 2 immune responses, TSLPR-deficient Tregs acquired TH2-like properties, with augmented GATA3 expression and secretion of IL-13. TSLP not only is a driver of TH2 effector cells but also acts in a negative feedback loop, thus promoting the ability of Tregs to limit allergic inflammation.
{"title":"TSLP acts on regulatory T cells to maintain their identity and limit allergic inflammation","authors":"Rama K. Gurram, Peng Li, Jangsuk Oh, Xi Chen, Rosanne Spolski, Xianglan Yao, Jian-Xin Lin, Suyasha Roy, Matthew J. Liao, Chengyu Liu, Zu-Xi Yu, Stewart J. Levine, Jinfang Zhu, Warren J. Leonard","doi":"10.1126/sciimmunol.adk0073","DOIUrl":"10.1126/sciimmunol.adk0073","url":null,"abstract":"<div >Thymic stromal lymphopoietin (TSLP) is a type I cytokine that promotes allergic responses and mediates type 2 immunity. A balance between effector T cells (T<sub>effs</sub>), which drive the immune response, and regulatory T cells (T<sub>regs</sub>), which suppress the response, is required for proper immune homeostasis. Here, we report that TSLP differentially acts on T<sub>effs</sub> versus T<sub>regs</sub> to balance type 2 immunity. As expected, deletion of TSLP receptor (TSLPR) on all T cells (<i>Cd4</i><sup>Cre</sup><i>Crlf2</i><sup>fl/fl</sup> mice) resulted in lower numbers of T helper 2 (T<sub>H</sub>2) cells and diminished ovalbumin-induced airway inflammation, but selective deletion of TSLPR on T<sub>regs</sub> (<i>Foxp3</i><sup><i>YFP</i>-Cre/Y</sup><i>Crlf2</i><sup>fl/fl</sup> mice) resulted in increased interleukin-5 (IL-5)– and IL-13–secreting T<sub>H</sub>2 cells and lung eosinophilia. Moreover, TSLP augmented the expression of factors that stabilize T<sub>regs</sub>. During type 2 immune responses, TSLPR-deficient T<sub>regs</sub> acquired T<sub>H</sub>2-like properties, with augmented GATA3 expression and secretion of IL-13. TSLP not only is a driver of T<sub>H</sub>2 effector cells but also acts in a negative feedback loop, thus promoting the ability of T<sub>regs</sub> to limit allergic inflammation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939924","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 : 2025-01-10DOI: 10.1126/sciimmunol.adq1697
Marita Bosticardo, Kerry Dobbs, Ottavia M. Delmonte, Andrew J. Martins, Francesca Pala, Tomoki Kawai, Heather Kenney, Gloria Magro, Lindsey B. Rosen, Yasuhiro Yamazaki, Hsin-Hui Yu, Enrica Calzoni, Yu Nee Lee, Can Liu, Jennifer Stoddard, Julie Niemela, Danielle Fink, Riccardo Castagnoli, Meredith Ramba, Aristine Cheng, Deanna Riley, Vasileios Oikonomou, Elana Shaw, Brahim Belaid, Sevgi Keles, Waleed Al-Herz, Caterina Cancrini, Cristina Cifaldi, Safa Baris, Svetlana Sharapova, Catharina Schuetz, Andrew R. Gennery, Alexandra F. Freeman, Raz Somech, Sharon Choo, Silvia C. Giliani, Tayfun Güngör, Daniel Drozdov, Isabelle Meyts, Despina Moshous, Benedicte Neven, Roshini S. Abraham, Aisha El-Marsafy, Maria Kanariou, Alejandra King, Francesco Licciardi, Mario E. Cruz-Muñoz, Paolo Palma, Cecilia Poli, Mehdi Adeli, Mattia Algeri, Fayhan J. Alroqi, Paul Bastard, Jenna R. E. Bergerson, Claire Booth, Ana Brett, Siobhan O. Burns, Manish J. Butte, Nurcicek Padem, M. Teresa de la Morena, Ghassan Dbaibo, Suk See de Ravin, Dimana Dimitrova, Reda Djidjik, Mayra B. Dorna, Cullen M. Dutmer, Reem Elfeky, Fabio Facchetti, Ramsay L. Fuleihan, Raif S. Geha, Luis I. Gonzalez-Granado, Liis Haljasmägi, Hanadys Ale, Anthony Hayward, Anna M. Hifanova, Winnie Ip, Blanka Kaplan, Neena Kapoor, Elif Karakoc-Aydiner, Jaanika Kärner, Michael D. Keller, Blachy J. Dávila Saldaña, Ayça Kiykim, Taco W. Kuijpers, Elena E. Kuznetsova, Elena A. Latysheva, Jennifer W. Leiding, Franco Locatelli, Guisela Alva-Lozada, Christine McCusker, Fatih Celmeli, Megan Morsheimer, Ahmet Ozen, Nima Parvaneh, Srdjan Pasic, Alessandro Plebani, Kahn Preece, Susan Prockop, Inga S. Sakovich, Elena E. Starkova, Troy Torgerson, James Verbsky, Jolan E. Walter, Brant Ward, Elizabeth L. Wisner, Deborah Draper, Katherine Myint-Hpu, Pooi M. Truong, Michail S. Lionakis, Morgan B. Similuk, Centralized Sequencing Program Group§§, Magdalena A. Walkiewicz, Amy Klion, Steven M. Holland, Cihan Oguz, Dusan Bogunovic, Kai Kisand, Helen C. Su, John S. Tsang, Douglas Kuhns, Anna Villa, Sergio D. Rosenzweig, Stefania Pittaluga, Luigi D. Notarangelo
Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of RAG-mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic RAG variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (TH2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage–specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease.
{"title":"Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature","authors":"Marita Bosticardo, Kerry Dobbs, Ottavia M. Delmonte, Andrew J. Martins, Francesca Pala, Tomoki Kawai, Heather Kenney, Gloria Magro, Lindsey B. Rosen, Yasuhiro Yamazaki, Hsin-Hui Yu, Enrica Calzoni, Yu Nee Lee, Can Liu, Jennifer Stoddard, Julie Niemela, Danielle Fink, Riccardo Castagnoli, Meredith Ramba, Aristine Cheng, Deanna Riley, Vasileios Oikonomou, Elana Shaw, Brahim Belaid, Sevgi Keles, Waleed Al-Herz, Caterina Cancrini, Cristina Cifaldi, Safa Baris, Svetlana Sharapova, Catharina Schuetz, Andrew R. Gennery, Alexandra F. Freeman, Raz Somech, Sharon Choo, Silvia C. Giliani, Tayfun Güngör, Daniel Drozdov, Isabelle Meyts, Despina Moshous, Benedicte Neven, Roshini S. Abraham, Aisha El-Marsafy, Maria Kanariou, Alejandra King, Francesco Licciardi, Mario E. Cruz-Muñoz, Paolo Palma, Cecilia Poli, Mehdi Adeli, Mattia Algeri, Fayhan J. Alroqi, Paul Bastard, Jenna R. E. Bergerson, Claire Booth, Ana Brett, Siobhan O. Burns, Manish J. Butte, Nurcicek Padem, M. Teresa de la Morena, Ghassan Dbaibo, Suk See de Ravin, Dimana Dimitrova, Reda Djidjik, Mayra B. Dorna, Cullen M. Dutmer, Reem Elfeky, Fabio Facchetti, Ramsay L. Fuleihan, Raif S. Geha, Luis I. Gonzalez-Granado, Liis Haljasmägi, Hanadys Ale, Anthony Hayward, Anna M. Hifanova, Winnie Ip, Blanka Kaplan, Neena Kapoor, Elif Karakoc-Aydiner, Jaanika Kärner, Michael D. Keller, Blachy J. Dávila Saldaña, Ayça Kiykim, Taco W. Kuijpers, Elena E. Kuznetsova, Elena A. Latysheva, Jennifer W. Leiding, Franco Locatelli, Guisela Alva-Lozada, Christine McCusker, Fatih Celmeli, Megan Morsheimer, Ahmet Ozen, Nima Parvaneh, Srdjan Pasic, Alessandro Plebani, Kahn Preece, Susan Prockop, Inga S. Sakovich, Elena E. Starkova, Troy Torgerson, James Verbsky, Jolan E. Walter, Brant Ward, Elizabeth L. Wisner, Deborah Draper, Katherine Myint-Hpu, Pooi M. Truong, Michail S. Lionakis, Morgan B. Similuk, Centralized Sequencing Program Group§§, Magdalena A. Walkiewicz, Amy Klion, Steven M. Holland, Cihan Oguz, Dusan Bogunovic, Kai Kisand, Helen C. Su, John S. Tsang, Douglas Kuhns, Anna Villa, Sergio D. Rosenzweig, Stefania Pittaluga, Luigi D. Notarangelo","doi":"10.1126/sciimmunol.adq1697","DOIUrl":"10.1126/sciimmunol.adq1697","url":null,"abstract":"<div >Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of <i>RAG</i>-mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic <i>RAG</i> variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (T<sub>H</sub>2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage–specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adq1697","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056081","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 : 2025-01-03DOI: 10.1126/sciimmunol.ads1556
Pradeep Ramalingam, Michael C. Gutkin, Michael G. Poulos, Agatha Winiarski, Arianna Smith, Cody Carter, Chelsea Doughty, Taylor Tillery, David Redmond, Ana G. Freire, Jason M. Butler
Chronic low-grade inflammation observed in older adults, termed inflammaging, is a common feature underlying a multitude of aging-associated maladies including a decline in hematopoietic activity. However, whether suppression of inflammaging can preserve hematopoietic health span remains unclear, in part because of a lack of tools to measure inflammaging within hematopoietic stem cells (HSCs). Here, we identify thrombospondin-1 (Thbs1) as an essential regulator of inflammaging within HSCs. We describe a transcriptomics-based approach for measuring inflammaging within stem cells and demonstrate that deletion of Thbs1 is sufficient to prevent HSC inflammaging. Our results demonstrate that suppression of HSC inflammaging prevents aging-associated defects in hematopoietic activity including loss of HSC self-renewal, myeloid-biased HSC differentiation, and anemia. Our findings indicate that suppression of HSC inflammaging may also prolong overall systemic health span.
{"title":"Suppression of thrombospondin-1–mediated inflammaging prolongs hematopoietic health span","authors":"Pradeep Ramalingam, Michael C. Gutkin, Michael G. Poulos, Agatha Winiarski, Arianna Smith, Cody Carter, Chelsea Doughty, Taylor Tillery, David Redmond, Ana G. Freire, Jason M. Butler","doi":"10.1126/sciimmunol.ads1556","DOIUrl":"10.1126/sciimmunol.ads1556","url":null,"abstract":"<div >Chronic low-grade inflammation observed in older adults, termed inflammaging, is a common feature underlying a multitude of aging-associated maladies including a decline in hematopoietic activity. However, whether suppression of inflammaging can preserve hematopoietic health span remains unclear, in part because of a lack of tools to measure inflammaging within hematopoietic stem cells (HSCs). Here, we identify thrombospondin-1 (Thbs1) as an essential regulator of inflammaging within HSCs. We describe a transcriptomics-based approach for measuring inflammaging within stem cells and demonstrate that deletion of <i>Thbs1</i> is sufficient to prevent HSC inflammaging. Our results demonstrate that suppression of HSC inflammaging prevents aging-associated defects in hematopoietic activity including loss of HSC self-renewal, myeloid-biased HSC differentiation, and anemia. Our findings indicate that suppression of HSC inflammaging may also prolong overall systemic health span.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ads1556","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917895","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 : 2025-01-03DOI: 10.1126/sciimmunol.adv4911
Jonathan Chuck, Laura A. Solt
A cell engineering approach demonstrates that precise regulation of cell signaling can be achieved using both endogenous and synthetic ligands.
细胞工程方法表明，利用内源配体和合成配体可以实现对细胞信号的精确调控。
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Pub Date : 2025-01-03DOI: 10.1126/sciimmunol.adl2993
Jie Xu, Lingzhi Zhang, Yanhui Duan, Fangyuan Sun, Nouha Odeh, Yuan He, Gabriel Núñez
The NLRP3 inflammasome plays a critical role in innate immunity and inflammatory diseases. NIMA-related kinase 7 (NEK7) is essential for inflammasome activation, and its interaction with NLRP3 is enhanced by K+ efflux. However, the mechanism by which K+ efflux promotes this interaction remains unknown. Here, we show that NEK7 is rapidly phosphorylated at threonine-190/191 by JNK1 downstream of K+ efflux and gasdermin D (GSDMD) after NLRP3 activation. NEK7 phosphorylation enhances the binding between NEK7 and NLRP3, which further promotes inflammasome assembly and activation. Mutant mice and macrophages in which Thr190 and Thr191 of Nek7 were replaced by valine exhibited impaired NEK7 phosphorylation, NLRP3 inflammasome activation, and IL-1β secretion. Thus, NEK7 phosphorylation is an important event that acts downstream of K+ efflux and GSDMD to further enhance NLRP3 inflammasome activation.
NLRP3炎症小体在先天免疫和炎症性疾病中起关键作用。nima相关激酶7 （NEK7）对炎性小体的激活至关重要，其与NLRP3的相互作用通过K +外排增强。然而，K +外溢促进这种相互作用的机制尚不清楚。在这里，我们发现NLRP3激活后，NEK7在苏氨酸-190/191位点被K +外排下游的JNK1和gasdermin D （GSDMD）快速磷酸化。NEK7磷酸化增强了NEK7与NLRP3之间的结合，从而进一步促进炎症小体的组装和激活。Nek7的Thr 190和Thr 191被缬氨酸取代的突变小鼠和巨噬细胞表现出Nek7磷酸化、NLRP3炎性体激活和IL-1β分泌受损。因此，NEK7磷酸化是一个重要的事件，它作用于K +外排和GSDMD下游，进一步增强NLRP3炎性体的激活。
{"title":"NEK7 phosphorylation amplifies NLRP3 inflammasome activation downstream of potassium efflux and gasdermin D","authors":"Jie Xu, Lingzhi Zhang, Yanhui Duan, Fangyuan Sun, Nouha Odeh, Yuan He, Gabriel Núñez","doi":"10.1126/sciimmunol.adl2993","DOIUrl":"10.1126/sciimmunol.adl2993","url":null,"abstract":"<div >The NLRP3 inflammasome plays a critical role in innate immunity and inflammatory diseases. NIMA-related kinase 7 (NEK7) is essential for inflammasome activation, and its interaction with NLRP3 is enhanced by K<sup>+</sup> efflux. However, the mechanism by which K<sup>+</sup> efflux promotes this interaction remains unknown. Here, we show that NEK7 is rapidly phosphorylated at threonine-190/191 by JNK1 downstream of K<sup>+</sup> efflux and gasdermin D (GSDMD) after NLRP3 activation. NEK7 phosphorylation enhances the binding between NEK7 and NLRP3, which further promotes inflammasome assembly and activation. Mutant mice and macrophages in which Thr<sup>190</sup> and Thr<sup>191</sup> of Nek7 were replaced by valine exhibited impaired NEK7 phosphorylation, NLRP3 inflammasome activation, and IL-1β secretion. Thus, NEK7 phosphorylation is an important event that acts downstream of K<sup>+</sup> efflux and GSDMD to further enhance NLRP3 inflammasome activation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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