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DOCK8 and STAT3 cooperate to restrain IgE-inducing T follicular helper cells. DOCK8和STAT3协同抑制ige诱导的T滤泡辅助细胞。
IF 10.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-03-02 Epub Date: 2026-01-28 DOI: 10.1084/jem.20241707
Emily R Siniscalco, Courtney Fisher, Meng-Ping Lu, Jessica D S Grassmann, Corinne D Mack, Roukaya Yaakoubi, Danielle Jacobsen, Qian Chen, Donguk Lee, Priya Rajamanimuthu, Tregony Simoneau, Kahn Preece, Paul Gray, Satoshi Okada, Bertrand Boisson, Basak Kayaoglu, Jeffrey Danielson, Alexandra F Freeman, Jean-Laurent Casanova, Talal A Chatila, Helen C Su, Cindy S Ma, Adam Williams, Stephanie C Eisenbarth, Uthaman Gowthaman

Patients with loss-of-function DOCK8 or dominant-negative STAT3 variants have hyper-IgE syndrome, although only DOCK8 deficiency consistently presents with elevated food-specific IgE and symptomatic allergy. We previously found in mice that DOCK8 restricts the differentiation of IL-13+ T follicular helper (Tfh13) cells that drive anaphylactic IgE, although the mechanisms were unclear. Here, we show that DOCK8 promotes STAT3 activity, which inhibits GATA3 in T cells. However, only patients with DOCK8, but not STAT3, deficiency had elevated Tfh13 cells. Cell-specific deletion of either Dock8 (T-Dock8-/-) or Stat3 (T-Stat3-/-) augmented peanut-specific IgE and Tfh13s when oral sensitization was promoted by adjuvants. However, the phenotypes diverged during adjuvant-free oral peanut exposure: only T-Dock8-/- mice developed Tfh13 cells and peanut-specific IgE, accompanied by reduced Foxp3+ Tregs. Treg depletion in T-Stat3-/- mice unmasked Tfh13 induction to oral antigen alone. Thus, DOCK8 and STAT3 cooperate to restrain Tfh13 differentiation to food allergens, and additional Treg impairment in DOCK8 deficiency allows for Tfh13 cell induction and allergy.

DOCK8功能丧失或STAT3显性阴性变异体的患者有高IgE综合征,尽管只有DOCK8缺乏症持续表现为食物特异性IgE升高和症状性过敏。我们之前在小鼠中发现,DOCK8限制了驱动过敏性IgE的IL-13+ T滤泡辅助细胞(Tfh13)的分化,尽管其机制尚不清楚。在这里,我们发现DOCK8促进STAT3活性,从而抑制T细胞中的GATA3。然而,只有DOCK8缺乏的患者,而不是STAT3缺乏的患者,Tfh13细胞升高。当佐剂促进口服致敏时,细胞特异性缺失Dock8 (T-Dock8-/-)或Stat3 (T-Stat3-/-)可增强花生特异性IgE和Tfh13s。然而,在无佐剂的口服花生暴露过程中,表型发生了分化:只有T-Dock8-/-小鼠产生了Tfh13细胞和花生特异性IgE,并伴有Foxp3+ Tregs的减少。T-Stat3-/-小鼠的Treg缺失揭示了Tfh13对口腔抗原的单独诱导。因此,DOCK8和STAT3协同抑制Tfh13向食物过敏原的分化,并且DOCK8缺乏时额外的Treg损伤允许Tfh13细胞诱导和过敏。
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引用次数: 0
Correction: B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2. 更正:B细胞对乳糜泻自身抗原转谷氨酰胺酶2的耐受性和抗体产生。
IF 10.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-03-02 Epub Date: 2026-02-12 DOI: 10.1084/jem.2019086002062026c
M Fleur du Pré, Jana Blazevski, Alisa E Dewan, Jorunn Stamnaes, Chakravarthi Kanduri, Geir Kjetil Sandve, Marie K Johannesen, Christian B Lindstad, Kathrin Hnida, Lars Fugger, Gerry Melino, Shuo-Wang Qiao, Ludvig M Sollid
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引用次数: 0
HIF-1-mediated ISG20 expression promotes breast cancer stemness and immune evasion. hif -1介导的ISG20表达促进乳腺癌的发生和免疫逃逸。
IF 10.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-03-02 Epub Date: 2025-12-12 DOI: 10.1084/jem.20250777
Yongkang Yang, Qiaozhu Zuo, Vijay Ramu, Varen Talwar, Yajing Lyu, Chelsey Chen, Daiana Drehmer, Tina Yi-Ting Huang, Shaima Salman, Dominic Dordai, Yufeng Wang, Emmanuel Datan, Elizabeth E Wicks, Gregg L Semenza

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the highest rates of recurrence, metastasis, and patient mortality due to the absence of effective therapies. Hypoxia-inducible factor 1 (HIF-1) regulates the expression of thousands of RNAs in TNBC. Here, we demonstrate that transcription of the ISG20 gene, which encodes an RNA exonuclease, is activated by HIF-1 in TNBC cells. ISG20-mediated degradation of RHOBTB3 mRNA increases HIF-1α protein expression and activates NANOG signaling, which increases breast cancer stem cell specification and lung metastasis. ISG20 also degrades STAT1 and IRF1 mRNAs, leading to decreased expression of CXCL10 and impaired recruitment of CD8+ T cells and natural killer cells, thereby promoting breast cancer immune evasion. Silencing ISG20 increases the sensitivity of mouse TNBC cells to anti-PD1 antibody immune checkpoint blockade. Our data suggest that targeting ISG20, in combination with immunotherapy, could be an effective therapeutic strategy for TNBC.

三阴性乳腺癌(TNBC)是最具侵袭性的乳腺癌亚型,由于缺乏有效的治疗,其复发、转移率和患者死亡率最高。缺氧诱导因子1 (HIF-1)调节TNBC中数千种rna的表达。在这里,我们证明了编码RNA外切酶的ISG20基因的转录在TNBC细胞中被HIF-1激活。isg20介导的RHOBTB3 mRNA降解增加HIF-1α蛋白表达,激活NANOG信号,从而增加乳腺癌干细胞分化和肺转移。ISG20还能降解STAT1和IRF1 mrna,导致CXCL10表达降低,CD8+ T细胞和自然杀伤细胞募集受损,从而促进乳腺癌免疫逃避。沉默ISG20可增加小鼠TNBC细胞对抗pd1抗体免疫检查点阻断的敏感性。我们的数据表明,靶向ISG20,结合免疫治疗,可能是治疗TNBC的有效策略。
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引用次数: 0
Autoantibodies neutralizing type I IFNs in patients with fulminant herpes simplex virus hepatitis. 暴发性单纯疱疹病毒性肝炎患者自身抗体中和I型干扰素的研究
IF 10.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-03-02 Epub Date: 2025-12-05 DOI: 10.1084/jem.20251760
Adrian Gervais, Astrid Marchal, Soraya Boucherit, Anthony Abi Haidar, Lucy Bizien, Ahmet Yalcinkaya, Ella Sandström, Xiao-Fei Kong, Emmanuel Jacquemin, Olivier Bernard, Dominique Debray, Florence Lacaille, Philippe Ichai, Cigdem Arikan, Etienne Javouhey, Bertrand Roquelaure, Frédéric Gottrand, Francesca Trespidi, Veronica Codullo, Lorenzo Cavagna, Nicolas Schleinitz, Mohamed Bousfiha, Naima Amenzoui, Ahmed Aziz Bousfiha, Sofie E Jørgensen, Nanna Mørk, Trine H Mogensen, Paul Bastard, Anne Puel, Alessandro Borghesi, Jody A Rule, William M Lee, Nils Landegren, Aurélie Cobat, Jean-Laurent Casanova, Emmanuelle Jouanguy

Fulminant viral hepatitis (FVH) is a devastating condition caused by hepatotropic viruses such as hepatitis A virus (HAV), hepatitis B virus (HBV), and HSV-1/2. We studied 149 FVH patients (73 males and 76 females, aged 1-76) for blood autoantibodies (auto-Abs) neutralizing type I interferons (IFNs; IFN-α2, -β, -ω). Six of 16 (37.5%) HSV-triggered FVH patients carried such auto-Abs on admission, including three with a previously known autoimmune disease. These patients contrasted with 133 HAV- (n = 46) or HBV-triggered (n = 87) patients, none of whom had such detectable auto-Abs. Odds ratios for HSV-triggered FVH in individuals with auto-Abs ranged from 35.3 (95% CI: 13.0-96.2; P < 10-7) for those neutralizing only 100 pg/ml IFN-α/ω to 1,895 (CI: 448.5-8,002; P < 10-12) for those neutralizing both IFN-α and IFN-ω at 10 ng/ml. Over one third of HSV-triggered FVH cases in this international cohort were due to preexisting auto-Abs. This finding highlights auto-Abs against type I IFNs as a major determinant of HSV-FVH and paves the way for targeted preventive or therapeutic interventions.

暴发性病毒性肝炎(FVH)是由嗜肝病毒(如甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)和HSV-1/2)引起的一种毁灭性疾病。我们研究了149例FVH患者(男性73例,女性76例,年龄1-76岁)的血液自身抗体(auto-Abs)中和I型干扰素(IFN; IFN-α2, -β, -ω)。16例hsv引发的FVH患者中有6例(37.5%)在入院时携带此类自身抗体,包括3例先前已知的自身免疫性疾病患者。这些患者与133例HAV- (n = 46)或hbv -触发(n = 87)患者形成对比,这些患者均未检测到此类自身抗体。对于仅中和100 pg/ml IFN-α/ω的自体抗体个体,hsv触发的FVH的优势比为35.3 (95% CI: 13.0-96.2; P < 10-7),对于同时中和10 ng/ml IFN-α和IFN-ω的个体,优势比为1,895 (CI: 448.5-8,002; P < 10-12)。在这一国际队列中,超过三分之一的单纯疱疹病毒引发的FVH病例是由于先前存在的自身抗体所致。这一发现强调了针对I型干扰素的自身抗体是HSV-FVH的主要决定因素,并为有针对性的预防或治疗干预铺平了道路。
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引用次数: 0
Autoantibodies neutralizing type I IFNs in a fatal case of H5N1 avian influenza. 在H5N1禽流感致命病例中,自身抗体中和I型干扰素。
IF 10.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-03-02 Epub Date: 2025-12-05 DOI: 10.1084/jem.20251962
Qian Zhang, Taylor S Conrad, Marcela Moncada-Velez, Kaijun Jiang, Anastasija Cupic, Jonathan Eaton, Kimberley Hutchinson, Adrian Gervais, Ruyue Chen, Anne Puel, Paul Bastard, Aurelie Cobat, Theresa Sokol, Ryan A Langlois, Lisa Miorin, Adolfo García-Sastre, John A Vanchiere, Jean-Laurent Casanova

Avian influenza A virus (IAV) H5N1 is an emerging threat of human pandemic. We describe a 71-year-old man who died of H5N1 pneumonia in Louisiana and whose blood contained autoantibodies neutralizing type I IFNs (AAN-I-IFNs), including the 12 IFN-α subtypes (1-10 ng/ml) and IFN-ω (100 pg/ml). Causality between these AAN-I-IFN and lethal outcome of avian influenza in this patient is based on (1) our previous report that AA-I-IFN underlie about 5% of cases of critical pneumonia triggered by seasonal influenza viruses in three cohorts, (2) the rarity of this combination of AAN-I-FNs in individuals over 70 years old (<1%), and (3) the rarity of lethal avian influenza among infected individuals (<1%). AAN-I-IFNs underlie a growing number of severe viral diseases, from arboviral encephalitis to viral pneumonia, particularly in the elderly. This case suggests they can also underlie life-threatening avian H5N1 influenza. The presence of AAN-I-IFN may facilitate infection, replication, and adaptation of zoonotic IAVs to humans and, therefore, human-to-human transmission.

H5N1型禽流感病毒(IAV)是一种新出现的人类大流行威胁。我们描述了一名在路易斯安那州死于H5N1肺炎的71岁男性,其血液中含有中和I型IFNs (AAN-I-IFNs)的自身抗体,包括12种IFN-α亚型(1-10 ng/ml)和IFN-ω (100 pg/ml)。这些AAN-I-IFN与该患者的禽流感致死结果之间的因果关系是基于(1)我们之前的报告,在三个队列中,大约5%的季节性流感病毒引发的重症肺炎病例是由AA-I-IFN引起的,(2)这种AAN-I-IFN组合在70岁以上个体中的罕见性(
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引用次数: 0
Transcription of HIV-1 is heterogenous among authentic latent CD4+ T cell clones. HIV-1的转录在真实的潜伏CD4+ T细胞克隆中是异质的。
IF 10.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-03-02 Epub Date: 2025-12-26 DOI: 10.1084/jem.20251584
Cintia Bittar, Ana Rafaela Teixeira, Thiago Y Oliveira, Gabriela S Silva Santos, Klara Lenart, Marcilio Jorge Fumagalli, Georg H J Weymar, Anna Kaczynska, Noemi L Linden, Isabella A T M Ferreira, Marina Caskey, R Brad Jones, Mila Jankovic, Michel C Nussenzweig

Antiretroviral therapy suppresses HIV-1 infection but fails to eliminate a reservoir of intact latent proviruses that reside primarily in CD4+ T cells. The lack of precise understanding of the latent compartment has made it challenging to develop curative strategies for HIV-1 infection. Here we report on the properties of CD4+ T cell clones carrying intact latent proviruses, expanded in vitro from single cells obtained from the reservoir of people living with HIV-1. The latent proviruses in the clones were integrated into ZNF genes, nongenic satellite, and centromeric regions, frequently associated with latency. Despite their descent from single cells, only a fraction of the cells (0.4-14%) expressed relatively low levels of HIV-1 that did not measurably alter host gene transcriptome. Latency-reversing agents (LRAs) variably increased expression, but the effects were modest and clone and LRA specific. The results suggest that pharmacologic and immunologic approaches to clear the reservoir should be optimized to accommodate intra- and inter-clonal diversity.

抗逆转录病毒治疗抑制HIV-1感染,但不能消除主要存在于CD4+ T细胞中的完整潜伏前病毒库。由于缺乏对潜伏区室的精确了解,开发HIV-1感染的治疗策略具有挑战性。在这里,我们报告了携带完整潜伏前病毒的CD4+ T细胞克隆的特性,从HIV-1感染者库中获得的单细胞在体外扩增。克隆中的潜伏原病毒被整合到ZNF基因、非基因卫星和着丝粒区,通常与潜伏期相关。尽管它们来自单个细胞,但只有一小部分细胞(0.4-14%)表达了相对较低水平的HIV-1,而这种水平并没有明显改变宿主基因转录组。延迟逆转剂(LRAs)不同程度地增加了表达,但作用是适度的,并且是克隆和LRA特异性的。结果表明,清除库的药理学和免疫学方法应该优化,以适应克隆内和克隆间的多样性。
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引用次数: 0
FOXO1 re-expression with a dual-recombinase allele rescues class switching in germinal center B cells. 在生发中心B细胞中,双重组酶等位基因fox01的重新表达挽救了类别转换。
IF 10.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-03-02 Epub Date: 2025-12-26 DOI: 10.1084/jem.20241136
Carlota Farré Díaz, Eleni Kabrani, Wiebke Winkler, Eric Blanc, Brigitte Wollert-Wulf, Claudia Salomon, F Thomas Wunderlich, Dieter Beule, Martin Janz, Klaus Rajewsky

Modeling complex (patho)physiological processes by sequential targeted mutagenesis in mice is limited by the lack of precision of cellular targeting and complex breeding strategies. We present a new Cre/DreERT2 dual-recombinase germinal center B cell (GCBC)-specific strain, with co-expression of the recombinases from a single allele. This enables highly efficient Cre-mediated FOXO1 knockout in GCBCs in vivo, followed by time-controlled, efficient Dre-mediated FOXO1 re-expression in the same cells, leading to functional rescue of GC compartmentalization and class switch recombination. The present approach can be easily adapted to other cellular contexts.

由于缺乏精确的细胞靶向和复杂的育种策略,在小鼠中通过顺序靶向诱变来模拟复杂的(病理)生理过程受到限制。我们提出了一种新的Cre/DreERT2双重组酶生发中心B细胞(GCBC)特异性菌株,具有来自单个等位基因的重组酶共表达。这使得体内GCBCs中高效的cre介导的FOXO1敲除,随后在同一细胞中进行时间控制的、高效的re介导的FOXO1重新表达,从而导致GC区隔化和类开关重组的功能恢复。目前的方法可以很容易地适应于其他细胞环境。
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引用次数: 0
In vivo CRISPR/Cas9 screens identify new regulators of B cell activation and plasma cell differentiation. 体内CRISPR/Cas9筛选发现B细胞活化和浆细胞分化的新调节因子。
IF 10.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-03-02 Epub Date: 2026-01-28 DOI: 10.1084/jem.20250594
Lesly Calderón, Markus Schäfer, Marina Rončević, René Rauschmeier, Markus Jaritz, Tanja A Schwickert, Qiong Sun, Andrea Pauli, Johannes Zuber, Meinrad Busslinger

Immune responses to pathogens lead to the generation of plasma cells through a complex interplay of B cells with their microenvironment in lymphoid organs. To identify new regulators of B cell activation and plasmablast differentiation in the context of the splenic microenvironment, we established an in vivo system for pooled sgRNA CRISPR/Cas9 screens in immunized mice. To improve the infection efficiency of naïve B cells, we generated Cd23-Cre Rosa26LSL-EcoR/+ mice exhibiting increased expression of the ecotropic lentivirus receptor EcoR on naïve B cells. Upon adoptive B cell transfer and immunization of recipient mice, 379 sgRNAs, targeting genes with high expression in plasma cells, were analyzed for their effects on plasmablast generation. Gene hits, encoding 23 positive and 18 negative regulators of B cell activation, plasmablast differentiation, or homeostasis, were uniquely identified in these in vivo screens. Validated genes encoded proteins involved in cell adhesion, signal transduction, protein folding, iron transport, and enzymatic processes. Hence, our in vivo screening system identified novel regulators controlling B cell-mediated immune responses.

对病原体的免疫反应通过B细胞与其淋巴器官微环境的复杂相互作用导致浆细胞的产生。为了鉴定脾脏微环境下B细胞活化和质母细胞分化的新调控因子,我们在免疫小鼠中建立了一个sgRNA CRISPR/Cas9混合筛选的体内系统。为了提高naïve B细胞的感染效率,我们产生了Cd23-Cre Rosa26LSL-EcoR/+小鼠,其在naïve B细胞上的亲生态慢病毒受体EcoR表达增加。通过受体小鼠的过继性B细胞转移和免疫,分析了379个针对浆细胞中高表达基因的sgrna对浆母细胞产生的影响。基因命中编码23个阳性和18个阴性的B细胞活化、质母细胞分化或体内平衡调节因子,在这些体内筛选中被唯一地鉴定出来。经过验证的基因编码的蛋白质参与细胞粘附、信号转导、蛋白质折叠、铁转运和酶促过程。因此,我们的体内筛选系统确定了控制B细胞介导的免疫反应的新调节因子。
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引用次数: 0
Antibiotic use in early life impairs MAIT cell-mediated immunity in adulthood. 生命早期使用抗生素会损害成年期MAIT细胞介导的免疫。
IF 10.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-03-02 Epub Date: 2025-12-16 DOI: 10.1084/jem.20241287
Gabrielle R LeBlanc, Adam L Sobel, Jonathan Melamed, Dominic Haas, Eduard Ansaldo, Aiko M Cirone, Elizabeth Murguia, Michael G Constantinides

Mucosal-associated invariant T (MAIT) cells are predominantly located in barrier tissues where they rapidly respond to pathogens and commensals by recognizing microbial derivatives of riboflavin synthesis. Early-life exposure to these metabolites imprints the abundance of MAIT cells within tissues, so we hypothesized that antibiotic use during this period may abrogate their development. We identified antibiotics that deplete riboflavin-synthesizing commensals and revealed an early period of susceptibility during which antibiotic administration impaired MAIT cell development. The reduction in MAIT cell abundance rendered mice more susceptible to pneumonia, while MAIT cell-deficient mice were unaffected by early-life antibiotics. Concomitant administration of a riboflavin-synthesizing commensal during antibiotic treatment was sufficient to restore MAIT cell development and immunity. Our work demonstrates that transient depletion of riboflavin-synthesizing commensals in early life can adversely affect responses to subsequent infections.

粘膜相关不变性T (MAIT)细胞主要位于屏障组织中,通过识别核黄素合成的微生物衍生物,对病原体和共生体迅速做出反应。早期接触这些代谢物会在组织中留下MAIT细胞丰度的印记,因此我们假设在这一时期使用抗生素可能会破坏它们的发育。我们发现抗生素会消耗核黄素合成共生体,并揭示了早期的易感性,在此期间抗生素给药会损害MAIT细胞的发育。MAIT细胞丰度的减少使小鼠更容易患肺炎,而MAIT细胞缺陷的小鼠不受早期抗生素的影响。在抗生素治疗期间同时给予核黄素合成共生体足以恢复MAIT细胞的发育和免疫。我们的研究表明,生命早期核黄素合成共生体的短暂耗竭会对后续感染的反应产生不利影响。
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引用次数: 0
Next-generation CRISPR screens enable causal systems immunology. 下一代CRISPR筛选使因果系统免疫学成为可能。
IF 10.6 1区 医学 Q1 IMMUNOLOGY Pub Date : 2026-03-02 Epub Date: 2026-02-19 DOI: 10.1084/jem.20241266
Hao Shi, Hongbo Chi

Mapping the causal circuits that shape the phenotypic and functional landscape of immune cells remains a formidable challenge. Recent advances in pooled CRISPR-based screens, coupled with multiplexed single-cell profiling and imaging-based spatial readouts, make this goal increasingly attainable. In this Perspective, we discuss how CRISPR-based genetic screens will fundamentally transform our understanding of immunobiology. We highlight the applications of state-of-the-art, high-throughput pooled perturbation approaches, including emerging methodologies for bulk, single-cell, and spatial CRISPR screens, to advance our understanding of immunity and in vivo biology. Additionally, we summarize new strategies to address the complexity of combinatorial perturbations to uncover genetic interactions and mechanistic drivers of immunity at unprecedented scale and resolution. By integrating CRISPR screening data with experimental insights, we advocate a new framework in immunology research that leverages perturbation-driven regulatory effects and networks to discover new therapeutic targets and establish causal systems biology and immunology for advancing immunological knowledge and therapeutic application.

绘制形成免疫细胞表型和功能景观的因果回路仍然是一项艰巨的挑战。基于crispr的聚合筛选技术的最新进展,加上多路单细胞分析和基于成像的空间读数,使这一目标越来越容易实现。在这个观点中,我们讨论了基于crispr的基因筛选将如何从根本上改变我们对免疫生物学的理解。我们强调了最先进的、高通量的混合扰动方法的应用,包括用于批量、单细胞和空间CRISPR筛选的新兴方法,以促进我们对免疫和体内生物学的理解。此外,我们总结了解决组合扰动复杂性的新策略,以前所未有的规模和分辨率揭示免疫的遗传相互作用和机制驱动因素。通过将CRISPR筛选数据与实验见解相结合,我们提倡在免疫学研究中建立一个新的框架,利用微扰驱动的调节效应和网络来发现新的治疗靶点,并建立因果系统生物学和免疫学,以推进免疫学知识和治疗应用。
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引用次数: 0
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