Pub Date : 2024-10-04DOI: 10.1126/sciimmunol.adt3806
Eli C. Olson, Stephanie C. Eisenbarth
Dendritic cells sense confinement in the environment to induce migration in the absence of typical inflammatory stimuli.
树突状细胞在没有典型炎症刺激的情况下，会感知环境中的局限性，从而诱导迁移。
{"title":"Dendritic cells in a pinch: Migration during homeostasis","authors":"Eli C. Olson, Stephanie C. Eisenbarth","doi":"10.1126/sciimmunol.adt3806","DOIUrl":"10.1126/sciimmunol.adt3806","url":null,"abstract":"<div >Dendritic cells sense confinement in the environment to induce migration in the absence of typical inflammatory stimuli.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375909","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}
The interferon (IFN) response is vital for the effectiveness of immune checkpoint inhibition (ICI) therapy. Our previous research showed that KRAS (Kirsten rat sarcoma viral) mutation impairs the IFN response in colorectal cancer (CRC), with an unclear mechanism. Here, we demonstrate that KRAS accelerates double-stranded RNA (dsRNA) degradation, impairing dsRNA sensing and IFN response by down-regulating DExD/H-box helicase 6 (DDX60). DDX60 was identified as a KRAS target here and could bind to dsRNAs to protect against RNA-induced silencing complex (RISC)–mediated degradation. Overexpressing DDX60 induced dsRNA accumulation, reactivated IFN signaling, and increased CRC sensitivity to ICI therapy. Mechanistically, KRAS engaged the AKT (also known as protein kinase B)–GSK3β (glycogen synthase kinase-3 beta) pathway to suppress STAT3 phosphorylation, thereby inhibiting STAT3-driven DDX60 transcription. Our findings reveal a role for KRAS in dsRNA homeostasis, suggesting potential strategies to convert “cold” tumors to “hot” and to overcome ICI resistance in CRC with KRAS mutations.
{"title":"Oncogenic KRAS drives immunosuppression of colorectal cancer by impairing DDX60-mediated dsRNA accumulation and viral mimicry","authors":"Yi Zhou, Yaxin Zhang, Mingzhou Li, Tian Ming, Chao Zhang, Chengmei Huang, Jiexi Li, Fengtian Li, Huali Li, Enen Zhao, Feng Shu, Lingtao Liu, Xingyan Pan, Yijun Gao, Lin Tian, Libing Song, Huilin Huang, Wenting Liao","doi":"10.1126/sciimmunol.ado8758","DOIUrl":"10.1126/sciimmunol.ado8758","url":null,"abstract":"<div >The interferon (IFN) response is vital for the effectiveness of immune checkpoint inhibition (ICI) therapy. Our previous research showed that KRAS (Kirsten rat sarcoma viral) mutation impairs the IFN response in colorectal cancer (CRC), with an unclear mechanism. Here, we demonstrate that KRAS accelerates double-stranded RNA (dsRNA) degradation, impairing dsRNA sensing and IFN response by down-regulating DExD/H-box helicase 6 (DDX60). DDX60 was identified as a KRAS target here and could bind to dsRNAs to protect against RNA-induced silencing complex (RISC)–mediated degradation. Overexpressing DDX60 induced dsRNA accumulation, reactivated IFN signaling, and increased CRC sensitivity to ICI therapy. Mechanistically, KRAS engaged the AKT (also known as protein kinase B)–GSK3β (glycogen synthase kinase-3 beta) pathway to suppress STAT3 phosphorylation, thereby inhibiting STAT3-driven DDX60 transcription. Our findings reveal a role for KRAS in dsRNA homeostasis, suggesting potential strategies to convert “cold” tumors to “hot” and to overcome ICI resistance in CRC with KRAS mutations.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374627","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 : 2024-10-04DOI: 10.1126/sciimmunol.adt4136
Anjali J. Panicker, Kevin C. O’Connor
Patients with autoimmune disease have exhausted antigen-specific T cells that remain capable of B cell support.
自身免疫性疾病患者的抗原特异性 T 细胞已经耗尽，但仍能支持 B 细胞。
{"title":"Tricky Ts play possum to propagate autoimmune disease","authors":"Anjali J. Panicker, Kevin C. O’Connor","doi":"10.1126/sciimmunol.adt4136","DOIUrl":"10.1126/sciimmunol.adt4136","url":null,"abstract":"<div >Patients with autoimmune disease have exhausted antigen-specific T cells that remain capable of B cell support.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375910","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 : 2024-10-04DOI: 10.1126/sciimmunol.ado0398
Katherine S. Forsyth, Natalie E. Toothacre, Nikhil Jiwrajka, Amanda M. Driscoll, Lindsey A. Shallberg, Charlotte Cunningham-Rundles, Sara Barmettler, Jocelyn Farmer, James Verbsky, John Routes, Daniel P. Beiting, Neil Romberg, Michael J. May, Montserrat C. Anguera
X chromosome inactivation (XCI) balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of X-inactive specific transcript (Xist) RNA and heterochromatic modifications on the inactive X chromosome (Xi), which are involved in maintenance of XCI, and these modifications return to the Xi after stimulation. Here, we examined allele-specific gene expression and epigenomic profiles of the Xi in T cells. We found that the Xi in unstimulated T cells is largely dosage compensated and enriched with the repressive H3K27me3 modification but not the H2AK119-ubiquitin (Ub) mark. Upon T cell stimulation mediated by both CD3 and CD28, the Xi accumulated H2AK119-Ub at gene regions of previous H3K27me3 enrichment. T cell receptor (TCR) engagement, specifically NF-κB signaling downstream of the TCR, was required for Xist RNA localization to the Xi. Disruption of NF-κB signaling in mouse and human T cells using genetic deletion, chemical inhibitors, and patients with immunodeficiencies prevented Xist/XIST RNA accumulation at the Xi and altered X-linked gene expression. Our findings reveal a previously undescribed connection between NF-κB signaling pathways, which affects XCI maintenance in T cells in females.
X 染色体失活（XCI）可平衡两性之间的 X 连锁基因剂量。未受刺激的T细胞缺乏细胞学富集的X-非活性特异性转录本（Xist）RNA和非活性X染色体（Xi）上的异染色质修饰，而这些修饰参与了XCI的维持。在这里，我们研究了T细胞中Xi的等位基因特异性基因表达和表观基因组图谱。我们发现，在未受刺激的 T 细胞中，Xi 在很大程度上受到剂量补偿，富含抑制性 H3K27me3 修饰，但不富含 H2AK119-泛素（Ub）标记。在 CD3 和 CD28 介导的 T 细胞刺激下，Xi 在先前 H3K27me3 富集的基因区域积累了 H2AK119-Ub。T细胞受体（TCR）的参与，特别是TCR下游的NF-κB信号，是Xist RNA定位到Xi的必要条件。利用基因缺失、化学抑制剂和免疫缺陷患者来破坏小鼠和人类 T 细胞中的 NF-κB 信号传导，可防止 Xist/XIST RNA 在 Xi 上的积累并改变 X 连锁基因的表达。我们的研究结果揭示了 NF-κB 信号通路之间以前未曾描述过的联系，这种联系会影响雌性 T 细胞中 XCI 的维持。
{"title":"Maintenance of X chromosome inactivation after T cell activation requires NF-κB signaling","authors":"Katherine S. Forsyth, Natalie E. Toothacre, Nikhil Jiwrajka, Amanda M. Driscoll, Lindsey A. Shallberg, Charlotte Cunningham-Rundles, Sara Barmettler, Jocelyn Farmer, James Verbsky, John Routes, Daniel P. Beiting, Neil Romberg, Michael J. May, Montserrat C. Anguera","doi":"10.1126/sciimmunol.ado0398","DOIUrl":"10.1126/sciimmunol.ado0398","url":null,"abstract":"<div >X chromosome inactivation (XCI) balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of X-inactive specific transcript (Xist) RNA and heterochromatic modifications on the inactive X chromosome (Xi), which are involved in maintenance of XCI, and these modifications return to the Xi after stimulation. Here, we examined allele-specific gene expression and epigenomic profiles of the Xi in T cells. We found that the Xi in unstimulated T cells is largely dosage compensated and enriched with the repressive H3K27me3 modification but not the H2AK119-ubiquitin (Ub) mark. Upon T cell stimulation mediated by both CD3 and CD28, the Xi accumulated H2AK119-Ub at gene regions of previous H3K27me3 enrichment. T cell receptor (TCR) engagement, specifically NF-κB signaling downstream of the TCR, was required for Xist RNA localization to the Xi. Disruption of NF-κB signaling in mouse and human T cells using genetic deletion, chemical inhibitors, and patients with immunodeficiencies prevented Xist/XIST RNA accumulation at the Xi and altered X-linked gene expression. Our findings reveal a previously undescribed connection between NF-κB signaling pathways, which affects XCI maintenance in T cells in females.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ado0398","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374663","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 : 2024-10-04DOI: 10.1126/sciimmunol.adq8843
Aleksey Chudnovskiy, Tiago B. R. Castro, Sandra Nakandakari-Higa, Ang Cui, Chia-Hao Lin, Moshe Sade-Feldman, Brooke K. Phillips, Juhee Pae, Luka Mesin, Juliana Bortolatto, Lawrence D. Schweitzer, Giulia Pasqual, Li-Fan Lu, Nir Hacohen, Gabriel D. Victora
Dendritic cells (DCs) are uniquely capable of transporting tumor antigens to tumor-draining lymph nodes (tdLNs) and interact with effector T cells in the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)–based single-cell transcriptomics, we identified individual DCs capable of presenting antigen to CD4+ T cells in both the tdLN and TME. Our findings revealed that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both in tumors and in the tdLN and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation in the tdLN and TME to both CD4+ and CD8+ tumor–specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.
树突状细胞（DC）具有独特的能力，能将肿瘤抗原运送到肿瘤引流淋巴结（tdLN），并与肿瘤微环境（TME）中的效应 T 细胞相互作用，介导天然抗肿瘤免疫和对检查点阻断免疫疗法的反应。利用基于单细胞转录组学的 LIPSTIC（通过 SorTagging 细胞间接触标记免疫伙伴关系），我们鉴定出了能够向tdLN 和 TME 中的 CD4 + T 细胞递呈抗原的单个 DC。我们的研究结果表明，具有类似超活化转录表型的DC在肿瘤和tdLN中都能与辅助T细胞相互作用，而检查点阻断药物能增强这些相互作用。这些研究结果表明，在tdLN和TME中，相对较小部分的DC负责向CD4 +和CD8 +肿瘤特异性T细胞呈递大部分抗原，而经典的检查点阻断药物能增强CD40驱动的DC在这两个部位的活化。
{"title":"Proximity-dependent labeling identifies dendritic cells that drive the tumor-specific CD4+ T cell response","authors":"Aleksey Chudnovskiy, Tiago B. R. Castro, Sandra Nakandakari-Higa, Ang Cui, Chia-Hao Lin, Moshe Sade-Feldman, Brooke K. Phillips, Juhee Pae, Luka Mesin, Juliana Bortolatto, Lawrence D. Schweitzer, Giulia Pasqual, Li-Fan Lu, Nir Hacohen, Gabriel D. Victora","doi":"10.1126/sciimmunol.adq8843","DOIUrl":"10.1126/sciimmunol.adq8843","url":null,"abstract":"<div >Dendritic cells (DCs) are uniquely capable of transporting tumor antigens to tumor-draining lymph nodes (tdLNs) and interact with effector T cells in the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)–based single-cell transcriptomics, we identified individual DCs capable of presenting antigen to CD4<sup>+</sup> T cells in both the tdLN and TME. Our findings revealed that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both in tumors and in the tdLN and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation in the tdLN and TME to both CD4<sup>+</sup> and CD8<sup>+</sup> tumor–specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374633","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 : 2024-09-27DOI: 10.1126/sciimmunol.adk7387
Jianglin Zhang, Guoxun Wang, Junjie Ma, Yiran Duan, Samskrathi A. Sharma, Sarah Oladejo, Xianda Ma, Giselle Arellano, Robert C. Orchard, Tiffany A. Reese, Zheng Kuang
The intestinal mucosal surface is directly exposed to daily fluctuations in food and microbes driven by 24-hour light and feeding cycles. Intestinal epithelial tuft cells are key sentinels that surveil the gut luminal environment, but how these cells are diurnally programmed remains unknown. Here, we show that histone deacetylase 3 (HDAC3) controls tuft cell specification and the diurnal rhythm of its biogenesis, which is regulated by the gut microbiota and feeding schedule. Disruption of epithelial HDAC3 decreases tuft cell numbers, impairing antihelminth immunity and norovirus infection. Mechanistically, HDAC3 functions noncanonically to activate transforming growth factor–β (TGF-β) signaling, which promotes rhythmic expression of Pou2f3, a lineage-defining transcription factor of tuft cells. Our findings reveal an environmental-epigenetic link that controls the diurnal differentiation of tuft cells and promotes rhythmic mucosal surveillance and immune responses in anticipation of exogenous challenges.
{"title":"HDAC3 integrates TGF-β and microbial cues to program tuft cell biogenesis and diurnal rhythms in mucosal immune surveillance","authors":"Jianglin Zhang, Guoxun Wang, Junjie Ma, Yiran Duan, Samskrathi A. Sharma, Sarah Oladejo, Xianda Ma, Giselle Arellano, Robert C. Orchard, Tiffany A. Reese, Zheng Kuang","doi":"10.1126/sciimmunol.adk7387","DOIUrl":"10.1126/sciimmunol.adk7387","url":null,"abstract":"<div >The intestinal mucosal surface is directly exposed to daily fluctuations in food and microbes driven by 24-hour light and feeding cycles. Intestinal epithelial tuft cells are key sentinels that surveil the gut luminal environment, but how these cells are diurnally programmed remains unknown. Here, we show that histone deacetylase 3 (HDAC3) controls tuft cell specification and the diurnal rhythm of its biogenesis, which is regulated by the gut microbiota and feeding schedule. Disruption of epithelial HDAC3 decreases tuft cell numbers, impairing antihelminth immunity and norovirus infection. Mechanistically, HDAC3 functions noncanonically to activate transforming growth factor–β (TGF-β) signaling, which promotes rhythmic expression of <i>Pou2f3</i>, a lineage-defining transcription factor of tuft cells. Our findings reveal an environmental-epigenetic link that controls the diurnal differentiation of tuft cells and promotes rhythmic mucosal surveillance and immune responses in anticipation of exogenous challenges.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 99","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325678","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 : 2024-09-27DOI: 10.1126/sciimmunol.adj8094
Vladyslav Kavaka, Luisa Mutschler, Clara de la Rosa del Val, Klara Eglseer, Ana M. Gómez Martínez, Andrea Flierl-Hecht, Birgit Ertl-Wagner, Daniel Keeser, Martin Mortazavi, Klaus Seelos, Hanna Zimmermann, Jürgen Haas, Brigitte Wildemann, Tania Kümpfel, Klaus Dornmair, Thomas Korn, Reinhard Hohlfeld, Martin Kerschensteiner, Lisa Ann Gerdes, Eduardo Beltrán
Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8+ T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8+ T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8+ T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS. Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8+ T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease.
多发性硬化症（MS）是中枢神经系统的一种炎症性神经疾病，在神经发炎之前有一个亚临床阶段。CD8 + T细胞在多发性硬化病灶中含量丰富，但它们在疾病病理中的潜在作用仍不清楚。利用高通量单细胞 RNA 测序和单细胞 T 细胞受体分析，我们比较了单卵双生子血液和脑脊液（CSF）中的 CD8 + T 细胞克隆，其中同卵双生子没有神经炎症或有亚临床神经炎症（SCNI）。我们发现了与多发性硬化症相关的外周免疫学和代谢改变，表明迁移性、促炎性和活化的 CD8 + T 细胞表型增强，这在患有 SCNI 的同卵双生子和多发性硬化症患者的独立验证队列中也很明显。总之，我们的深入单细胞分析表明了浸润的 CD8 + T 细胞对疾病的促炎作用，并确定了疾病前驱期和终末期的潜在免疫学和代谢治疗靶点。
{"title":"Twin study identifies early immunological and metabolic dysregulation of CD8+ T cells in multiple sclerosis","authors":"Vladyslav Kavaka, Luisa Mutschler, Clara de la Rosa del Val, Klara Eglseer, Ana M. Gómez Martínez, Andrea Flierl-Hecht, Birgit Ertl-Wagner, Daniel Keeser, Martin Mortazavi, Klaus Seelos, Hanna Zimmermann, Jürgen Haas, Brigitte Wildemann, Tania Kümpfel, Klaus Dornmair, Thomas Korn, Reinhard Hohlfeld, Martin Kerschensteiner, Lisa Ann Gerdes, Eduardo Beltrán","doi":"10.1126/sciimmunol.adj8094","DOIUrl":"10.1126/sciimmunol.adj8094","url":null,"abstract":"<div >Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8<sup>+</sup> T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8<sup>+</sup> T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8<sup>+</sup> T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS. Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8<sup>+</sup> T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 99","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adj8094","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325683","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 : 2024-09-20DOI: 10.1126/sciimmunol.adl3755
Sachin H. Bhagchandani, Leerang Yang, Jonathan H. Lam, Laura Maiorino, Elana Ben-Akiva, Kristen A. Rodrigues, Anna Romanov, Heikyung Suh, Aereas Aung, Shengwei Wu, Anika Wadhera, Arup K. Chakraborty, Darrell J. Irvine
Prolonging exposure to subunit vaccines during the primary immune response enhances humoral immunity. Escalating-dose immunization (EDI), administering vaccines every other day in an increasing pattern over 2 weeks, is particularly effective but challenging to implement clinically. Here, using an HIV Env trimer/saponin adjuvant vaccine, we explored simplified EDI regimens and found that a two-shot regimen administering 20% of the vaccine followed by the remaining 80% of the dose 7 days later increased TFH responses 6-fold, antigen-specific germinal center (GC) B cells 10-fold, and serum antibody titers 10-fold compared with bolus immunization. Computational modeling of TFH priming and the GC response suggested that enhanced activation/antigen loading on dendritic cells and increased capture of antigen delivered in the second dose by follicular dendritic cells contribute to these effects, predictions we verified experimentally. These results suggest that a two-shot priming approach can be used to substantially enhance responses to subunit vaccines.
在初级免疫反应期间延长亚单位疫苗的接种时间可增强体液免疫。递增剂量免疫接种（EDI）是指在两周内以递增的方式隔天接种疫苗，这种方法特别有效，但在临床上实施却很困难。在这里，我们使用一种 HIV Env 三聚体/皂素佐剂疫苗探索了简化的 EDI 方案，并发现与栓剂免疫法相比，先注射 20% 疫苗，7 天后再注射剩余 80% 疫苗的两针方案可使 TFH 反应增加 6 倍，抗原特异性生殖中心 (GC) B 细胞增加 10 倍，血清抗体滴度增加 10 倍。TFH启动和GC反应的计算模型表明，树突状细胞的活化/抗原负载增强以及滤泡树突状细胞对第二剂抗原的捕获增加有助于产生这些效应，我们在实验中验证了这一预测。这些结果表明，两针引物法可以大大提高亚单位疫苗的应答。
{"title":"Two-dose priming immunization amplifies humoral immunity by synchronizing vaccine delivery with the germinal center response","authors":"Sachin H. Bhagchandani, Leerang Yang, Jonathan H. Lam, Laura Maiorino, Elana Ben-Akiva, Kristen A. Rodrigues, Anna Romanov, Heikyung Suh, Aereas Aung, Shengwei Wu, Anika Wadhera, Arup K. Chakraborty, Darrell J. Irvine","doi":"10.1126/sciimmunol.adl3755","DOIUrl":"10.1126/sciimmunol.adl3755","url":null,"abstract":"<div >Prolonging exposure to subunit vaccines during the primary immune response enhances humoral immunity. Escalating-dose immunization (EDI), administering vaccines every other day in an increasing pattern over 2 weeks, is particularly effective but challenging to implement clinically. Here, using an HIV Env trimer/saponin adjuvant vaccine, we explored simplified EDI regimens and found that a two-shot regimen administering 20% of the vaccine followed by the remaining 80% of the dose 7 days later increased T<sub>FH</sub> responses 6-fold, antigen-specific germinal center (GC) B cells 10-fold, and serum antibody titers 10-fold compared with bolus immunization. Computational modeling of T<sub>FH</sub> priming and the GC response suggested that enhanced activation/antigen loading on dendritic cells and increased capture of antigen delivered in the second dose by follicular dendritic cells contribute to these effects, predictions we verified experimentally. These results suggest that a two-shot priming approach can be used to substantially enhance responses to subunit vaccines.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 99","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adl3755","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275197","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 : 2024-09-20DOI: 10.1126/sciimmunol.adp3475
Darren R. Heintzman, Rachael C. Sinard, Emilie L. Fisher, Xiang Ye, Andrew R. Patterson, Joel H. Elasy, Kelsey Voss, Channing Chi, Ayaka Sugiura, Gabriel J. Rodriguez-Garcia, Nowrin U. Chowdhury, Emily N. Arner, Evan S. Krystoviak, Frank M. Mason, Yasmine T. Toudji, KayLee K. Steiner, Wasay Khan, Lana M. Olson, Angela L. Jones, Hanna S. Hong, Lindsay Bass, Katherine L. Beier, Wentao Deng, Costas A. Lyssiotis, Dawn C. Newcomb, Alexander G. Bick, W. Kimryn Rathmell, John T. Wilson, Jeffrey C. Rathmell
Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (TH1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many TH1 cells subjected to such temperatures died, surviving TH1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to TH1 cells. TH1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of TH1 cells to maintain genomic integrity and enhance effector functions.
热是炎症的一个主要特征，但它对免疫细胞的影响仍不确定。我们的研究表明，中度发热温度（39°C）会增加小鼠 CD4 T 细胞的新陈代谢、增殖和炎症效应活性，同时降低调节性 T 细胞的抑制能力。然而，受热的 T 辅助细胞 1（T H 1）会选择性地出现线粒体应激和 DNA 损伤，从而激活 Trp53 和干扰素基因刺激因子通路。虽然在这种温度下许多 T H 1 细胞死亡，但存活下来的 T H 1 细胞线粒体质量增加，活性增强。电子传递链复合物 1（ETC1）在发热范围的温度下迅速受损，这种现象对 T H 1 细胞特别不利。在人类慢性炎症中也检测到 T H 1 细胞的 DNA 损伤和 ETC1 标志升高。因此，发烧相关温度会破坏 ETC1，从而选择性地驱动 T H 1 细胞凋亡或适应，以保持基因组完整性并增强效应功能。
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Pub Date : 2024-09-13DOI: 10.1126/sciimmunol.adi3487
Duncan M. Morgan, Brendan L. Horton, Vidit Bhandarkar, Richard Van, Teresa Dinter, Maria Zagorulya, J. Christopher Love, Stefani Spranger
Immune checkpoint blockade (ICB) enhances T cell responses against cancer, leading to long-term survival in a fraction of patients. CD8+ T cell differentiation in response to chronic antigen stimulation is highly complex, and it remains unclear precisely which T cell differentiation states at which anatomic sites are critical for the response to ICB. We identified an intermediate-exhausted population in the white pulp of the spleen that underwent substantial expansion in response to ICB and gave rise to tumor-infiltrating clonotypes. Increased systemic antigen redirected differentiation of this population toward a more circulatory exhausted KLR state, whereas a lack of cross-presented tumor antigen reduced its differentiation in the spleen. An analogous population of exhausted KLR CD8+ T cells in human blood samples exhibited diminished tumor-trafficking ability. Collectively, our data demonstrate the critical role of antigen density within the spleen for the differentiation and expansion of T cell clonotypes in response to ICB.
免疫检查点阻断（ICB）可增强T细胞对癌症的反应，从而使一部分患者长期存活。应对慢性抗原刺激的 CD8+ T 细胞分化非常复杂，目前仍不清楚哪些解剖部位的 T 细胞分化状态对 ICB 的反应至关重要。我们在脾脏白髓中发现了一个中间衰竭群体，它在对 ICB 作出反应时发生了大量扩增，并产生了肿瘤浸润克隆型。全身抗原的增加使这一群体向循环衰竭的 KLR 状态重新分化，而交叉呈现的肿瘤抗原的缺乏则减少了其在脾脏中的分化。人体血液样本中类似的枯竭 KLR CD8+ T 细胞群表现出较低的肿瘤牵引能力。总之，我们的数据证明了脾脏内的抗原密度对 T 细胞克隆型对 ICB 的分化和扩增起着至关重要的作用。
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