Pub Date : 2024-08-23DOI: 10.1126/sciimmunol.adn2717
Alessio Bevilacqua, Fabien Franco, Ya-Ting Lu, Nabil Rahiman, Kung-Chi Kao, Yu-Ming Chuang, Yanan Zhu, Werner Held, Xin Xie, Kristin C. Gunsalus, Zhengtao Xiao, Shih-Yu Chen, Ping-Chih Ho
The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator–activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.
记忆 T 细胞的形成是适应性免疫的一个基本特征，它允许建立针对病原体的长期保护。尽管新出现的证据表明，代谢重编程对记忆 T 细胞的分化和存活至关重要，但驱动记忆 T 细胞代谢重编程的潜在机制仍不清楚。在这里，我们发现核受体过氧化物酶体增殖激活受体β/δ（PPARβ/δ）的上调指导了中枢记忆CD8+ T细胞建立过程中发生的代谢重编程。PPARβ/δ调控的变化包括抑制有氧糖酵解，增强氧化代谢和脂肪酸氧化。从机制上讲，暴露于白细胞介素-15和T细胞因子1的表达促进了PPARβ/δ途径的激活，抵消了抗原清除和代谢压力诱导的细胞凋亡。总之，我们的研究结果表明，PPARβ/δ 是一种主代谢调节因子，它协调着一种可能有利于 T 细胞长寿的代谢转换。
{"title":"PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells","authors":"Alessio Bevilacqua, Fabien Franco, Ya-Ting Lu, Nabil Rahiman, Kung-Chi Kao, Yu-Ming Chuang, Yanan Zhu, Werner Held, Xin Xie, Kristin C. Gunsalus, Zhengtao Xiao, Shih-Yu Chen, Ping-Chih Ho","doi":"10.1126/sciimmunol.adn2717","DOIUrl":"10.1126/sciimmunol.adn2717","url":null,"abstract":"<div >The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator–activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8<sup>+</sup> T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044165","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 : 2024-08-23DOI: 10.1126/sciimmunol.adk3469
Merve Aksöz, Grigore-Aristide Gafencu, Bilyana Stoilova, Mario Buono, Ying Zhang, Sven Turkalj, Yiran Meng, Niels Asger Jakobsen, Marlen Metzner, Sally-Ann Clark, Ryan Beveridge, Supat Thongjuea, Paresh Vyas, Claus Nerlov
Hematopoietic stem cells (HSCs) reconstitute multilineage human hematopoiesis after clinical bone marrow (BM) transplantation and are the cells of origin of some hematological malignancies. Although HSCs provide multilineage engraftment, individual murine HSCs are lineage biased and contribute unequally to blood cell lineages. Here, we performed high-throughput single-cell RNA sequencing in mice after xenograft with molecularly barcoded adult human BM HSCs. We demonstrated that human individual BM HSCs are also functionally and transcriptionally lineage biased. Specifically, we identified platelet-biased and multilineage human HSCs. Quantitative comparison of transcriptomes from single HSCs from young and aged BM showed that both the proportion of platelet-biased HSCs and their level of transcriptional platelet priming increase with age. Therefore, platelet-biased HSCs and their increased prevalence and transcriptional platelet priming during aging are conserved features of mammalian evolution.
{"title":"Hematopoietic stem cell heterogeneity and age-associated platelet bias are evolutionarily conserved","authors":"Merve Aksöz, Grigore-Aristide Gafencu, Bilyana Stoilova, Mario Buono, Ying Zhang, Sven Turkalj, Yiran Meng, Niels Asger Jakobsen, Marlen Metzner, Sally-Ann Clark, Ryan Beveridge, Supat Thongjuea, Paresh Vyas, Claus Nerlov","doi":"10.1126/sciimmunol.adk3469","DOIUrl":"10.1126/sciimmunol.adk3469","url":null,"abstract":"<div >Hematopoietic stem cells (HSCs) reconstitute multilineage human hematopoiesis after clinical bone marrow (BM) transplantation and are the cells of origin of some hematological malignancies. Although HSCs provide multilineage engraftment, individual murine HSCs are lineage biased and contribute unequally to blood cell lineages. Here, we performed high-throughput single-cell RNA sequencing in mice after xenograft with molecularly barcoded adult human BM HSCs. We demonstrated that human individual BM HSCs are also functionally and transcriptionally lineage biased. Specifically, we identified platelet-biased and multilineage human HSCs. Quantitative comparison of transcriptomes from single HSCs from young and aged BM showed that both the proportion of platelet-biased HSCs and their level of transcriptional platelet priming increase with age. Therefore, platelet-biased HSCs and their increased prevalence and transcriptional platelet priming during aging are conserved features of mammalian evolution.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044163","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 : 2024-08-23DOI: 10.1126/sciimmunol.adh0545
Philipp Starkl, Gustav Jonsson, Tyler Artner, Bruna Lenfers Turnes, Laura-Marie Gail, Tiago Oliveira, Aakanksha Jain, Nadine Serhan, Karel Stejskal, Karin Lakovits, Anastasiya Hladik, Meilin An, Keith M. Channon, Hail Kim, Thomas Köcher, Wolfgang Weninger, Georg Stary, Sylvia Knapp, Victoria Klang, Nicolas Gaudenzio, Clifford J. Woolf, Shweta Tikoo, Rohit Jain, Josef M. Penninger, Shane J. F. Cronin
Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell–specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P–driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.
大多数患者在接受大手术后都会出现术后疼痛，并有可能转变为慢性疼痛。目前的治疗方法副作用大、疗效有限，因此需要新的治疗方案。我们观察到皮肤损伤后代谢物 BH4 和血清素的含量增加。肥大细胞是术后 Gch1 的主要来源，Gch1 是 BH4 合成过程中的限速酶，本身也是色氨酸羟化酶（Tph1）产生血清素的必备辅助因子。缺乏肥大细胞或肥大细胞特异性 Gch1 或 Tph1 的小鼠术后疼痛明显减轻。我们发现，损伤会诱导痛觉神经肽物质 P、肥大细胞脱颗粒和颗粒神经共定位。物质 P 能诱导小鼠和人类肥大细胞释放血清素，而物质 P 受体阻断能显著改善痛觉过敏性。我们的研究结果突显了肥大细胞在神经免疫界面的重要性，以及物质 P 驱动肥大细胞 BH4 和血清素分泌作为术后疼痛治疗靶点的重要性。
{"title":"Mast cell–derived BH4 and serotonin are critical mediators of postoperative pain","authors":"Philipp Starkl, Gustav Jonsson, Tyler Artner, Bruna Lenfers Turnes, Laura-Marie Gail, Tiago Oliveira, Aakanksha Jain, Nadine Serhan, Karel Stejskal, Karin Lakovits, Anastasiya Hladik, Meilin An, Keith M. Channon, Hail Kim, Thomas Köcher, Wolfgang Weninger, Georg Stary, Sylvia Knapp, Victoria Klang, Nicolas Gaudenzio, Clifford J. Woolf, Shweta Tikoo, Rohit Jain, Josef M. Penninger, Shane J. F. Cronin","doi":"10.1126/sciimmunol.adh0545","DOIUrl":"10.1126/sciimmunol.adh0545","url":null,"abstract":"<div >Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of <i>Gch1</i>, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell–specific <i>Gch1</i> or <i>Tph1</i> showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P–driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044164","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 : 2024-08-16DOI: 10.1126/sciimmunol.ade7530
Leandro P. Araujo, Madeline Edwards, Koichiro Irie, Yiming Huang, Yoshinaga Kawano, Alexander Tran, Simona De Michele, Govind Bhagat, Harris H. Wang, Ivaylo I. Ivanov
How group 3 innate lymphoid cells (ILC3s) regulate mucosal protection in the presence of T cells remains poorly understood. Here, we examined ILC3 function in intestinal immunity using ILC3-deficient mice that maintain endogenous T cells, T helper 17 (TH17) cells, and secondary lymphoid organs. ILC3s were dispensable for generation of TH17 and TH22 cell responses to commensal and pathogenic bacteria, and absence of ILC3s did not affect IL-22 production by CD4 T cells before or during infection. However, despite the presence of IL-22–producing T cells, ILC3s and ILC3-derived IL-22 were required for maintaining homeostatic functions of the intestinal epithelium. T cell–sufficient, ILC3-deficient mice were capable of pathogen clearance and survived infection with a low dose of Citrobacter rodentium. However, ILC3s promoted pathogen tolerance at early time points of infection by activating tissue-protective immune pathways. Consequently, ILC3s were indispensable for survival after high-dose infection. Our results demonstrate a context-dependent role for ILC3s in immune-sufficient animals and provide a blueprint for uncoupling of ILC3 and TH17 cell functions.
{"title":"Context-dependent role of group 3 innate lymphoid cells in mucosal protection","authors":"Leandro P. Araujo, Madeline Edwards, Koichiro Irie, Yiming Huang, Yoshinaga Kawano, Alexander Tran, Simona De Michele, Govind Bhagat, Harris H. Wang, Ivaylo I. Ivanov","doi":"10.1126/sciimmunol.ade7530","DOIUrl":"10.1126/sciimmunol.ade7530","url":null,"abstract":"<div >How group 3 innate lymphoid cells (ILC3s) regulate mucosal protection in the presence of T cells remains poorly understood. Here, we examined ILC3 function in intestinal immunity using ILC3-deficient mice that maintain endogenous T cells, T helper 17 (T<sub>H</sub>17) cells, and secondary lymphoid organs. ILC3s were dispensable for generation of T<sub>H</sub>17 and T<sub>H</sub>22 cell responses to commensal and pathogenic bacteria, and absence of ILC3s did not affect IL-22 production by CD4 T cells before or during infection. However, despite the presence of IL-22–producing T cells, ILC3s and ILC3-derived IL-22 were required for maintaining homeostatic functions of the intestinal epithelium. T cell–sufficient, ILC3-deficient mice were capable of pathogen clearance and survived infection with a low dose of <i>Citrobacter rodentium</i>. However, ILC3s promoted pathogen tolerance at early time points of infection by activating tissue-protective immune pathways. Consequently, ILC3s were indispensable for survival after high-dose infection. Our results demonstrate a context-dependent role for ILC3s in immune-sufficient animals and provide a blueprint for uncoupling of ILC3 and T<sub>H</sub>17 cell functions.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992387","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 : 2024-08-16DOI: 10.1126/sciimmunol.adr9665
{"title":"Erratum for the Research Article “SARS-CoV-2 inflammation durably imprints memory CD4 T cells” by S. L. Gray-Gaillard et al.","authors":"","doi":"10.1126/sciimmunol.adr9665","DOIUrl":"10.1126/sciimmunol.adr9665","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992388","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 : 2024-08-16DOI: 10.1126/sciimmunol.adh0368
Andrew R. Patterson, Gabriel A. Needle, Ayaka Sugiura, Erin Q. Jennings, Channing Chi, KayLee K. Steiner, Emilie L. Fisher, Gabriella L. Robertson, Caroline Bodnya, Janet G. Markle, Ryan D. Sheldon, Russell G. Jones, Vivian Gama, Jeffrey C. Rathmell
Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable previously unappreciated crossover. Analysis of IEMs showed that N-linked glycosylation and the hexosamine pathway enzyme Gfpt1 are critical for T cell expansion and function. Further, T helper (TH1) cells synthesized uridine diphosphate N-acetylglucosamine more rapidly and were more impaired by Gfpt1 deficiency than TH17 cells. Screening IEI genes found that Bcl11b promotes the CD4 T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. Thus, a high degree of functional overlap exists between IEM and IEI genes, and immunometabolic mechanisms may underlie a previously underappreciated intersection of these disorders.
先天性代谢错误（IEMs）和免疫（IEIs）是孟德尔疾病，其复杂的表型和患者的罕见性限制了临床了解。虽然很少有基因被注释为对 IEMs 和 IEIs 都有影响，但免疫代谢需求表明它们在功能上有更大的重叠。在这里，CRISPR 筛选测试了 IEM 基因的免疫学作用和 IEI 基因的代谢作用，发现了大量以前未曾注意到的交叉。对 IEM 的分析表明，N-连接的糖基化和六聚糖途径酶 Gfpt1 对 T 细胞的扩增和功能至关重要。此外，与 T H 17 细胞相比，T 辅助细胞（T H 1）合成尿苷二磷酸 N - 乙酰葡糖胺的速度更快，而且 Gfpt1 缺乏对其损害更大。对 IEI 基因的筛选发现，Bcl11b 可促进 CD4 T 细胞线粒体活性和 Mcl1 的表达，这是防止代谢压力所必需的。因此，IEM 和 IEI 基因之间存在着高度的功能重叠，免疫代谢机制可能是以前未被重视的这些疾病交叉的基础。
{"title":"Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities","authors":"Andrew R. Patterson, Gabriel A. Needle, Ayaka Sugiura, Erin Q. Jennings, Channing Chi, KayLee K. Steiner, Emilie L. Fisher, Gabriella L. Robertson, Caroline Bodnya, Janet G. Markle, Ryan D. Sheldon, Russell G. Jones, Vivian Gama, Jeffrey C. Rathmell","doi":"10.1126/sciimmunol.adh0368","DOIUrl":"10.1126/sciimmunol.adh0368","url":null,"abstract":"<div >Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable previously unappreciated crossover. Analysis of IEMs showed that N-linked glycosylation and the hexosamine pathway enzyme <i>Gfpt1</i> are critical for T cell expansion and function. Further, T helper (T<sub>H</sub>1) cells synthesized uridine diphosphate <i>N</i>-acetylglucosamine more rapidly and were more impaired by <i>Gfpt1</i> deficiency than T<sub>H</sub>17 cells. Screening IEI genes found that <i>Bcl11b</i> promotes the CD4 T cell mitochondrial activity and <i>Mcl1</i> expression necessary to prevent metabolic stress. Thus, a high degree of functional overlap exists between IEM and IEI genes, and immunometabolic mechanisms may underlie a previously underappreciated intersection of these disorders.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992052","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 : 2024-08-09DOI: 10.1126/sciimmunol.adr7181
{"title":"Erratum for the Research Article “TGF-β specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf” by Y. Chang et al.","authors":"","doi":"10.1126/sciimmunol.adr7181","DOIUrl":"10.1126/sciimmunol.adr7181","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141910109","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 : 2024-08-09DOI: 10.1126/sciimmunol.adp9279
Ida Paciello, Giuseppe Maccari, Giulio Pierleoni, Federica Perrone, Giulia Realini, Marco Troisi, Gabriele Anichini, Maria Grazia Cusi, Rino Rappuoli, Emanuele Andreano
The severe acute respiratory syndrome coronavirus 2 variant JN.1 recently emerged as the dominant variant despite having only one amino acid change on the spike (S) protein receptor binding domain (RBD) compared with the ancestral BA.2.86, which never represented more than 5% of global variants. To define at the molecular level the JN.1 ability to spread globally, we interrogated a panel of 899 neutralizing human monoclonal antibodies. Our data show that the single leucine-455–to–serine mutation in the JN.1 spike protein RBD unleashed the global spread of JN.1, likely occurring by elimination of more than 70% of the neutralizing antibodies mediated by IGHV3-53/3-66 germlines. However, the resilience of class 3 antibodies with low neutralization potency but strong Fc functions may explain the absence of JN.1 severe disease.
{"title":"SARS-CoV-2 JN.1 variant evasion of IGHV3-53/3-66 B cell germlines","authors":"Ida Paciello, Giuseppe Maccari, Giulio Pierleoni, Federica Perrone, Giulia Realini, Marco Troisi, Gabriele Anichini, Maria Grazia Cusi, Rino Rappuoli, Emanuele Andreano","doi":"10.1126/sciimmunol.adp9279","DOIUrl":"10.1126/sciimmunol.adp9279","url":null,"abstract":"<div >The severe acute respiratory syndrome coronavirus 2 variant JN.1 recently emerged as the dominant variant despite having only one amino acid change on the spike (S) protein receptor binding domain (RBD) compared with the ancestral BA.2.86, which never represented more than 5% of global variants. To define at the molecular level the JN.1 ability to spread globally, we interrogated a panel of 899 neutralizing human monoclonal antibodies. Our data show that the single leucine-455–to–serine mutation in the JN.1 spike protein RBD unleashed the global spread of JN.1, likely occurring by elimination of more than 70% of the neutralizing antibodies mediated by IGHV3-53/3-66 germlines. However, the resilience of class 3 antibodies with low neutralization potency but strong Fc functions may explain the absence of JN.1 severe disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp9279","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141910110","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 : 2024-08-09DOI: 10.1126/sciimmunol.add4874
Mukta Deobagkar-Lele, Greg Crawford, Tanya L. Crockford, Jennifer Back, Rose Hodgson, Aneesha Bhandari, Katherine R. Bull, Richard J. Cornall
Dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome is characterized by a failure of the germinal center response, a process involving the proliferation and positive selection of antigen-specific B cells. Here, we describe how DOCK8-deficient B cells are blocked at a light-zone checkpoint in the germinal centers of immunized mice, where they are unable to respond to T cell–dependent survival and selection signals and consequently differentiate into plasma cells or memory B cells. Although DOCK8-deficient B cells can acquire and present antigen to initiate activation of cognate T cells, integrin up-regulation, B cell–T cell conjugate formation, and costimulation are insufficient for sustained B cell and T cell activation when antigen availability is limited. Our findings provide an explanation for the failure of the humoral response in DOCK8 immunodeficiency syndrome and insight into how the level of available antigen modulates B cell–T cell cross-talk to fine-tune humoral immune responses and immunological memory.
细胞因子发生器 8（DOCK8）免疫缺陷综合征的特征是生殖中心反应失败，这一过程涉及抗原特异性 B 细胞的增殖和阳性选择。在这里，我们描述了 DOCK8 缺失的 B 细胞如何在免疫小鼠生殖中心的光区检查点受阻，无法对 T 细胞依赖的存活和选择信号做出反应，从而分化成浆细胞或记忆 B 细胞。虽然 DOCK8 缺失的 B 细胞可以获取并呈现抗原以启动同源 T 细胞的活化，但当抗原供应有限时，整合素上调、B 细胞-T 细胞结合体形成和成本刺激不足以实现 B 细胞和 T 细胞的持续活化。我们的研究结果解释了 DOCK8 免疫缺陷综合征中体液反应失败的原因，并深入探讨了可用抗原水平如何调节 B 细胞-T 细胞交叉对话，以微调体液免疫反应和免疫记忆。
{"title":"B cells require DOCK8 to elicit and integrate T cell help when antigen is limiting","authors":"Mukta Deobagkar-Lele, Greg Crawford, Tanya L. Crockford, Jennifer Back, Rose Hodgson, Aneesha Bhandari, Katherine R. Bull, Richard J. Cornall","doi":"10.1126/sciimmunol.add4874","DOIUrl":"10.1126/sciimmunol.add4874","url":null,"abstract":"<div >Dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome is characterized by a failure of the germinal center response, a process involving the proliferation and positive selection of antigen-specific B cells. Here, we describe how DOCK8-deficient B cells are blocked at a light-zone checkpoint in the germinal centers of immunized mice, where they are unable to respond to T cell–dependent survival and selection signals and consequently differentiate into plasma cells or memory B cells. Although DOCK8-deficient B cells can acquire and present antigen to initiate activation of cognate T cells, integrin up-regulation, B cell–T cell conjugate formation, and costimulation are insufficient for sustained B cell and T cell activation when antigen availability is limited. Our findings provide an explanation for the failure of the humoral response in DOCK8 immunodeficiency syndrome and insight into how the level of available antigen modulates B cell–T cell cross-talk to fine-tune humoral immune responses and immunological memory.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141910108","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 : 2024-08-09DOI: 10.1126/sciimmunol.adk9872
Alejandro Marin-Lopez, John D. Huck, Allen T. Esterly, Veronica Azcutia, Connor Rosen, Rolando Garcia-Milian, Esen Sefik, Gemma Vidal-Pedrola, Hamidah Raduwan, Tse-Yu Chen, Gunjan Arora, Stephanie Halene, Albert C. Shaw, Noah W. Palm, Richard A. Flavell, Charles A. Parkos, Saravanan Thangamani, Aaron M. Ring, Erol Fikrig
The Aedes aegypti mosquito is a vector of many infectious agents, including flaviviruses such as Zika virus. Components of mosquito saliva have pleomorphic effects on the vertebrate host to enhance blood feeding, and these changes also create a favorable niche for pathogen replication and dissemination. Here, we demonstrate that human CD47, which is known to be involved in various immune processes, interacts with a 34-kilodalton mosquito salivary protein named Nest1. Nest1 is up-regulated in blood-fed female A. aegypti and facilitates Zika virus dissemination in human skin explants. Nest1 has a stronger affinity for CD47 than its natural ligand, signal regulatory protein α, competing for binding at the same interface. The interaction between Nest1 with CD47 suppresses phagocytosis by human macrophages and inhibits proinflammatory responses by white blood cells, thereby suppressing antiviral responses in the skin. This interaction elucidates how an arthropod protein alters the human response to promote arbovirus infectivity.
{"title":"The human CD47 checkpoint is targeted by an immunosuppressive Aedes aegypti salivary factor to enhance arboviral skin infectivity","authors":"Alejandro Marin-Lopez, John D. Huck, Allen T. Esterly, Veronica Azcutia, Connor Rosen, Rolando Garcia-Milian, Esen Sefik, Gemma Vidal-Pedrola, Hamidah Raduwan, Tse-Yu Chen, Gunjan Arora, Stephanie Halene, Albert C. Shaw, Noah W. Palm, Richard A. Flavell, Charles A. Parkos, Saravanan Thangamani, Aaron M. Ring, Erol Fikrig","doi":"10.1126/sciimmunol.adk9872","DOIUrl":"10.1126/sciimmunol.adk9872","url":null,"abstract":"<div >The <i>Aedes aegypti</i> mosquito is a vector of many infectious agents, including flaviviruses such as Zika virus. Components of mosquito saliva have pleomorphic effects on the vertebrate host to enhance blood feeding, and these changes also create a favorable niche for pathogen replication and dissemination. Here, we demonstrate that human CD47, which is known to be involved in various immune processes, interacts with a 34-kilodalton mosquito salivary protein named Nest1. Nest1 is up-regulated in blood-fed female <i>A. aegypti</i> and facilitates Zika virus dissemination in human skin explants. Nest1 has a stronger affinity for CD47 than its natural ligand, signal regulatory protein α, competing for binding at the same interface. The interaction between Nest1 with CD47 suppresses phagocytosis by human macrophages and inhibits proinflammatory responses by white blood cells, thereby suppressing antiviral responses in the skin. This interaction elucidates how an arthropod protein alters the human response to promote arbovirus infectivity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141910111","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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