Immunity最新文献_第2页

Computationally designed proteins mimic antibody immune evasion in viral evolution 计算设计的蛋白质模拟病毒进化中的抗体免疫逃避

IF 32.4 1区医学

Immunity Pub Date : 2025-05-08 DOI: 10.1016/j.immuni.2025.04.015

Noor Youssef, Sarah Gurev, Fadi Ghantous, Kelly P. Brock, Javier A. Jaimes, Nicole N. Thadani, Ann Dauphin, Amy C. Sherman, Leonid Yurkovetskiy, Daria Soto, Ralph Estanboulieh, Ben Kotzen, Pascal Notin, Aaron W. Kollasch, Alexander A. Cohen, Sandra E. Dross, Jesse Erasmus, Deborah H. Fuller, Pamela J. Bjorkman, Jacob E. Lemieux, Debora S. Marks

{"title":"Computationally designed proteins mimic antibody immune evasion in viral evolution","authors":"Noor Youssef, Sarah Gurev, Fadi Ghantous, Kelly P. Brock, Javier A. Jaimes, Nicole N. Thadani, Ann Dauphin, Amy C. Sherman, Leonid Yurkovetskiy, Daria Soto, Ralph Estanboulieh, Ben Kotzen, Pascal Notin, Aaron W. Kollasch, Alexander A. Cohen, Sandra E. Dross, Jesse Erasmus, Deborah H. Fuller, Pamela J. Bjorkman, Jacob E. Lemieux, Debora S. Marks","doi":"10.1016/j.immuni.2025.04.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.015","url":null,"abstract":"Recurrent waves of viral infection necessitate vaccines and therapeutics that remain effective against emerging viruses. Our ability to evaluate interventions is currently limited to assessments against past or circulating variants, which likely differ in their immune escape potential compared with future variants. To address this, we developed EVE-Vax, a computational method for designing antigens that foreshadow immune escape observed in future viral variants. We designed 83 SARS-CoV-2 spike proteins that transduced ACE2-positive cells and displayed neutralization resistance comparable to variants that emerged up to 12 months later in the COVID-19 pandemic. Designed spikes foretold antibody escape from B.1-BA.4/5 bivalent booster sera seen in later variants. The designed constructs also highlighted the increased neutralization breadth elicited by nanoparticle-based, compared with mRNA-based, boosters in non-human primates. Our approach offers targeted panels of synthetic proteins that map the immune landscape for early vaccine and therapeutic evaluation against future viral strains.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"54 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920770","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}

引用次数: 0

Somatic hypermutation unlocks antibody specificities beyond the primary repertoire 体细胞超突变解锁抗体特异性超出了主要曲目

IF 32.4 1区医学

Immunity Pub Date : 2025-05-07 DOI: 10.1016/j.immuni.2025.04.014

Teng Zuo, Avneesh Gautam, Shahab Saghaei, Sweta N. Khobragade, Rahaman Ahmed, Azadeh Mahdavinia, Mehrdad Zarghami, Gaspar A. Pacheco, Kenneth Green, Meghan Travers, Nicholas Garcia, Zahra Allahyari, Vishal Rao, Sachin Kumar, Robert Novak, Joyce K. Hwang, Duane R. Wesemann

{"title":"Somatic hypermutation unlocks antibody specificities beyond the primary repertoire","authors":"Teng Zuo, Avneesh Gautam, Shahab Saghaei, Sweta N. Khobragade, Rahaman Ahmed, Azadeh Mahdavinia, Mehrdad Zarghami, Gaspar A. Pacheco, Kenneth Green, Meghan Travers, Nicholas Garcia, Zahra Allahyari, Vishal Rao, Sachin Kumar, Robert Novak, Joyce K. Hwang, Duane R. Wesemann","doi":"10.1016/j.immuni.2025.04.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.014","url":null,"abstract":"B cell somatic hypermutation (SHM) and selection in germinal centers (GCs) enhance antibody affinity for antigen. Here, we investigated whether SHM-based antibody evolution is restricted to specificities established through V(D)J recombination in the primary repertoire. Tracking pre-defined non-specific B cells across multiple immunization models revealed that non-cognate B cells within GCs undergo SHM. Under conditions of limited B cell competition, these B cells generated <em>de novo</em> antigen recognition to multiple epitopes across diverse model antigens. Phylogenetic analyses identified diverse mutational pathways leading to new antigen affinities, and enhanced T cell co-stimulation further promoted new antigen recognition. Our data support a model in which B cell competition—rather than an intrinsic requirement for specific affinity—limits the emergence of new affinities through SHM, highlighting the mammalian adaptive immune system’s ability to explore antibody-antigen interactions beyond those encoded by the V(D)J-dependent primary repertoire, demonstrating the flexibility of SHM in not only ripening but also reshaping specificity.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"50 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915709","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}

引用次数: 0

Vaccination of nonhuman primates elicits a broadly neutralizing antibody lineage targeting a quaternary epitope on the HIV-1 Env trimer 非人灵长类动物的疫苗接种引发了一种广泛中和的抗体谱系，靶向HIV-1 Env三聚体上的一个四级表位

IF 32.4 1区医学

Immunity Pub Date : 2025-05-07 DOI: 10.1016/j.immuni.2025.04.010

Fabian-Alexander Schleich, Shridhar Bale, Javier Guenaga, Gabriel Ozorowski, Monika Àdori, Xiaohe Lin, Xaquin Castro Dopico, Richard Wilson, Mark Chernyshev, Alma Teresia Cotgreave, Marco Mandolesi, Jocelyn Cluff, Esmeralda D. Doyle, Leigh M. Sewall, Wen-Hsin Lee, Shiyu Zhang, Sijy O’Dell, Brandon S. Healy, Deuk Lim, Vanessa R. Lewis, Richard T. Wyatt

{"title":"Vaccination of nonhuman primates elicits a broadly neutralizing antibody lineage targeting a quaternary epitope on the HIV-1 Env trimer","authors":"Fabian-Alexander Schleich, Shridhar Bale, Javier Guenaga, Gabriel Ozorowski, Monika Àdori, Xiaohe Lin, Xaquin Castro Dopico, Richard Wilson, Mark Chernyshev, Alma Teresia Cotgreave, Marco Mandolesi, Jocelyn Cluff, Esmeralda D. Doyle, Leigh M. Sewall, Wen-Hsin Lee, Shiyu Zhang, Sijy O’Dell, Brandon S. Healy, Deuk Lim, Vanessa R. Lewis, Richard T. Wyatt","doi":"10.1016/j.immuni.2025.04.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.010","url":null,"abstract":"The elicitation of cross-neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) by vaccination remains a major challenge. Here, we immunized previously Env-immunized nonhuman primates with a series of near-native trimers that possessed N-glycan deletions proximal to the conserved CD4 binding site (CD4bs) to focus B cells to this region. Following heterologous boosting with fully glycosylated trimers, we detected tier 2 cross-neutralizing activity in the serum of several animals. Isolation of 185 matched heavy- and light-chain sequences from Env-binding memory B cells from an early responder identified a broadly neutralizing antibody lineage, LJF-0034, which neutralized nearly 70% of an 84-member HIV-1 global panel. High-resolution cryoelectron microscopy (cryo-EM) structures revealed a bifurcated binding mode that bridged the CD4bs to V3 across the gp120:120 interface on two adjacent protomers, evading the proximal N276 glycan impediment to the CD4bs, allowing neutralization breadth. This quaternary epitope defines a potential target for future HIV-1 vaccine development.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"141 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915708","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}

引用次数: 0

Phosphoantigen-induced inside-out stabilization of butyrophilin receptor complexes drives dimerization-dependent γδ TCR activation 磷酸抗原诱导的亲丁酸蛋白受体复合物的内向外稳定驱动二聚化依赖性γδ TCR激活

IF 32.4 1区医学

Immunity Pub Date : 2025-05-06 DOI: 10.1016/j.immuni.2025.04.012

Yuwei Zhu, Wenbo Gao, Jianlin Zheng, Ye Bai, Xinyu Tian, Tengjin Huang, Zebin Lu, De Dong, Anqi Zhang, Changyou Guo, Zhiwei Huang

{"title":"Phosphoantigen-induced inside-out stabilization of butyrophilin receptor complexes drives dimerization-dependent γδ TCR activation","authors":"Yuwei Zhu, Wenbo Gao, Jianlin Zheng, Ye Bai, Xinyu Tian, Tengjin Huang, Zebin Lu, De Dong, Anqi Zhang, Changyou Guo, Zhiwei Huang","doi":"10.1016/j.immuni.2025.04.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.012","url":null,"abstract":"Phosphoantigens (pAgs), produced by infected or cancer cells, trigger the assembly of a membrane receptor complex comprising butyrophilin (BTN) members BTN3A1 and BTN2A1, leading to the activation of γδ T cells. BTN3A2 or BTN3A3 forms heteromers with BTN3A1, exhibiting higher γδ T cell receptor (TCR)-stimulating activity than BTN3A1 homomers. Cryoelectron microscopy (cryo-EM) structure reveals a pAg-induced BTN2A1-BTN3A1 heterotetramer with a 2:2 stoichiometry, stabilized by interactions between the intracellular B30.2 domains and the extracellular immunoglobulin V (IgV) domains. BTN3A2 or BTN3A3 heterodimerizes with BTN3A1, forming a pAg-induced tetrameric complex with BTN2A1. However, BTN3A1 heterodimers are more stable than BTN3A1 homodimers in this interaction. Cryo-EM reveals that BTN2A1-BTN3A1-BTN3A2 binds two γδ TCR ectodomains, with one being sandwiched between the IgV domains of BTN2A1 and BTN3A2, while the other interacts with the free BTN2A1 IgV in the complex, as evidenced by functional data. Together, our findings uncover the mechanism of ligand-induced inside-out stabilization of BTN receptor complexes for dimeric activation of γδ TCR.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"20 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910630","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}

引用次数: 0

Microglia transcriptional states and their functional significance: Context drives diversity 小胶质细胞转录状态及其功能意义：环境驱动多样性

IF 32.4 1区医学

Immunity Pub Date : 2025-05-06 DOI: 10.1016/j.immuni.2025.04.009

Constanze Depp, Jordan L. Doman, Maximilian Hingerl, Judy Xia, Beth Stevens

引用次数: 0

Niche-specific therapeutic targeting of myeloid cells in the central nervous system 中枢神经系统骨髓细胞的靶向治疗

IF 32.4 1区医学

Immunity Pub Date : 2025-05-04 DOI: 10.1016/j.immuni.2025.03.016

Maximilian Frosch, Marco Prinz

引用次数: 0

Glymphatics and meningeal lymphatics unlock the brain-immune code 淋巴细胞学和脑膜淋巴学解开了大脑免疫密码