Pub Date : 2024-09-30DOI: 10.1016/j.immuni.2024.08.018
Alexander Lercher, Jin-Gyu Cheong, Michael J. Bale, Chenyang Jiang, Hans-Heinrich Hoffmann, Alison W. Ashbrook, Tyler Lewy, Yue S. Yin, Corrine Quirk, Emma J. DeGrace, Luis Chiriboga, Brad R. Rosenberg, Steven Z. Josefowicz, Charles M. Rice
Pathogen encounter can result in epigenetic remodeling that shapes disease caused by heterologous pathogens. Here, we examined innate immune memory in the context of commonly circulating respiratory viruses. Single-cell analyses of airway-resident immune cells in a disease-relevant murine model of SARS-CoV-2 recovery revealed epigenetic reprogramming in alveolar macrophages following infection. Post-COVID-19 human monocytes exhibited similar epigenetic signatures. In airway-resident macrophages, past SARS-CoV-2 infection increased activity of type I interferon (IFN-I)-related transcription factors and epigenetic poising of antiviral genes. Viral pattern recognition and canonical IFN-I signaling were required for the establishment of this innate immune memory and augmented secondary antiviral responses. Antiviral innate immune memory mounted by airway-resident macrophages post-SARS-CoV-2 was necessary and sufficient to ameliorate secondary disease caused by influenza A virus and curtailed hyperinflammatory dysregulation and mortality. Our findings provide insights into antiviral innate immune memory in the airway that may facilitate the development of broadly effective therapeutic strategies.
病原体相遇会导致表观遗传重塑,从而形成由异源病原体引起的疾病。在此,我们研究了常见呼吸道循环病毒背景下的先天免疫记忆。在一个与疾病相关的 SARS-CoV-2 恢复小鼠模型中,对气道驻留免疫细胞的单细胞分析显示,肺泡巨噬细胞在感染后发生了表观遗传重编程。COVID-19 后的人类单核细胞也表现出类似的表观遗传特征。在气道驻留的巨噬细胞中,过去的 SARS-CoV-2 感染增加了 I 型干扰素(IFN-I)相关转录因子的活性和抗病毒基因的表观遗传学定位。这种先天性免疫记忆的建立需要病毒模式识别和典型的 IFN-I 信号传导,并增强了继发性抗病毒反应。SARS-CoV-2后气道驻留巨噬细胞建立的抗病毒先天性免疫记忆对于改善甲型流感病毒引起的继发性疾病、减少高炎症失调和死亡率是必要且充分的。我们的研究结果为了解气道中的抗病毒先天免疫记忆提供了见解,这可能有助于开发广泛有效的治疗策略。
{"title":"Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection ameliorates secondary influenza A virus disease","authors":"Alexander Lercher, Jin-Gyu Cheong, Michael J. Bale, Chenyang Jiang, Hans-Heinrich Hoffmann, Alison W. Ashbrook, Tyler Lewy, Yue S. Yin, Corrine Quirk, Emma J. DeGrace, Luis Chiriboga, Brad R. Rosenberg, Steven Z. Josefowicz, Charles M. Rice","doi":"10.1016/j.immuni.2024.08.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.018","url":null,"abstract":"Pathogen encounter can result in epigenetic remodeling that shapes disease caused by heterologous pathogens. Here, we examined innate immune memory in the context of commonly circulating respiratory viruses. Single-cell analyses of airway-resident immune cells in a disease-relevant murine model of SARS-CoV-2 recovery revealed epigenetic reprogramming in alveolar macrophages following infection. Post-COVID-19 human monocytes exhibited similar epigenetic signatures. In airway-resident macrophages, past SARS-CoV-2 infection increased activity of type I interferon (IFN-I)-related transcription factors and epigenetic poising of antiviral genes. Viral pattern recognition and canonical IFN-I signaling were required for the establishment of this innate immune memory and augmented secondary antiviral responses. Antiviral innate immune memory mounted by airway-resident macrophages post-SARS-CoV-2 was necessary and sufficient to ameliorate secondary disease caused by influenza A virus and curtailed hyperinflammatory dysregulation and mortality. Our findings provide insights into antiviral innate immune memory in the airway that may facilitate the development of broadly effective therapeutic strategies.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"23 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360547","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 : 2024-09-30DOI: 10.1016/j.immuni.2024.09.002
Ye Liu, Yifang Chen, Uyanga Batzorig, Jingting Li, Celia Fernández-Méndez, Samiksha Mahapatra, Fengwu Li, Shebin Sam, Tatsuya Dokoshi, Seung-Phil Hong, Teruaki Nakatsuji, Richard L. Gallo, George L. Sen
The surface of the skin is continually exposed to pro-inflammatory stimuli; however, it is unclear why it is not constantly inflamed due to this exposure. Here, we showed undifferentiated keratinocytes residing in the deep epidermis could trigger a strong inflammatory response due to their high expression of pattern recognition receptors (PRRs) that detect damage or pathogens. As keratinocytes differentiated, they migrated outward toward the surface of the skin and decreased their PRR expression, which led to dampened immune responses. ZNF750, a transcription factor expressed only in differentiated keratinocytes, recruited the histone demethylase KDM1A/LSD1 to silence genes coding for PRRs (TLR3, IFIH1/MDA5, and DDX58/RIG1). Loss of ZNF750 or KDM1A in human keratinocytes or mice resulted in sustained and excessive inflammation resembling psoriatic skin, which could be restored to homeostatic conditions upon silencing of TLR3. Our findings explain how the skin’s surface prevents excessive inflammation through ZNF750- and KDM1A-mediated suppression of PRRs.
{"title":"The transcription regulators ZNF750 and LSD1/KDM1A dampen inflammation on the skin’s surface by silencing pattern recognition receptors","authors":"Ye Liu, Yifang Chen, Uyanga Batzorig, Jingting Li, Celia Fernández-Méndez, Samiksha Mahapatra, Fengwu Li, Shebin Sam, Tatsuya Dokoshi, Seung-Phil Hong, Teruaki Nakatsuji, Richard L. Gallo, George L. Sen","doi":"10.1016/j.immuni.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.002","url":null,"abstract":"The surface of the skin is continually exposed to pro-inflammatory stimuli; however, it is unclear why it is not constantly inflamed due to this exposure. Here, we showed undifferentiated keratinocytes residing in the deep epidermis could trigger a strong inflammatory response due to their high expression of pattern recognition receptors (PRRs) that detect damage or pathogens. As keratinocytes differentiated, they migrated outward toward the surface of the skin and decreased their PRR expression, which led to dampened immune responses. ZNF750, a transcription factor expressed only in differentiated keratinocytes, recruited the histone demethylase KDM1A/LSD1 to silence genes coding for PRRs (<em>TLR3</em>, <em>IFIH1</em>/MDA5, and <em>DDX58</em>/RIG1). Loss of ZNF750 or KDM1A in human keratinocytes or mice resulted in sustained and excessive inflammation resembling psoriatic skin, which could be restored to homeostatic conditions upon silencing of <em>TLR3</em>. Our findings explain how the skin’s surface prevents excessive inflammation through ZNF750- and KDM1A-mediated suppression of PRRs.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"18 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330274","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}
As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that Il34 is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8+ T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation.
作为癌症中最常见的基因改变,一半以上的人类癌症都有导致转录失活的 p53 突变。然而,p53如何调节免疫格局以创造一个免疫逃逸的生态位仍是个谜。我们发现,在p53失活的肝癌中,癌症干细胞(CSCs)建立了一个由白细胞介素-34(IL-34)协调的生态位来促进肿瘤发生。从机理上讲,我们发现Il34是一种受p53转录抑制的基因,p53缺失导致CSCs分泌IL-34。IL-34诱导CD36介导的脂肪酸氧化代谢升高,从而推动泡沫样肿瘤相关巨噬细胞(TAMs)的M2样极化。这些由 IL-34 促成的 TAMs 可抑制 CD8+ T 细胞介导的抗肿瘤免疫,从而促进免疫逃逸。阻断IL-34-CD36轴可激发抗肿瘤免疫,并与抗PD-1免疫疗法协同作用,导致完全应答。我们的研究结果揭示了p53调节肿瘤免疫微环境的潜在机制,并为p53失活的癌症免疫疗法提供了潜在靶点。
{"title":"Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation","authors":"Zhigang Nian, Yingchao Dou, Yiqing Shen, Jintang Liu, Xianghui Du, Yong Jiang, Yonggang Zhou, Binqing Fu, Rui Sun, Xiaohu Zheng, Zhigang Tian, Haiming Wei","doi":"10.1016/j.immuni.2024.08.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.015","url":null,"abstract":"As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that <em>Il34</em> is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8<sup>+</sup> T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"34 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313575","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 : 2024-09-24DOI: 10.1016/j.immuni.2024.08.019
Pavla Bohacova, Marina Terekhova, Petr Tsurinov, Riley Mullins, Kamila Husarcikova, Irina Shchukina, Alina Ulezko Antonova, Barbora Echalar, Jan Kossl, Adam Saidu, Thomas Francis, Chelsea Mannie, Laura Arthur, Stephen D.R. Harridge, Daniel Kreisel, Philip A. Mudd, Angela M. Taylor, Coleen A. McNamara, Marina Cella, Sidharth V. Puram, Maxim N. Artyomov
Thymic involution is a key factor in human immune aging, leading to reduced thymic output and a decline in recent thymic emigrant (RTE) naive T cells in circulation. Currently, the precise definition of human RTEs and their corresponding cell surface markers lacks clarity. Analysis of single-cell RNA-seq/ATAC-seq data distinguished RTEs by the expression of SOX4, IKZF2, and TOX and CD38 protein, whereby surface CD38hi expression universally identified CD8+ and CD4+ RTEs. We further determined the dynamics of RTEs and mature cells in a cohort of 158 individuals, including age-associated transcriptional reprogramming and shifts in cytokine production. Spectral cytometry profiling revealed two axes of aging common to naive CD8+ and CD4+ T cells: (1) a decrease in CD38++ cells (RTEs) and (2) an increase in CXCR3hi cells. Identification of RTEs enables direct assessment of thymic health. Furthermore, resolving the dynamics of naive T cell remodeling yields insight into vaccination and infection responsiveness throughout aging.
{"title":"Multidimensional profiling of human T cells reveals high CD38 expression, marking recent thymic emigrants and age-related naive T cell remodeling","authors":"Pavla Bohacova, Marina Terekhova, Petr Tsurinov, Riley Mullins, Kamila Husarcikova, Irina Shchukina, Alina Ulezko Antonova, Barbora Echalar, Jan Kossl, Adam Saidu, Thomas Francis, Chelsea Mannie, Laura Arthur, Stephen D.R. Harridge, Daniel Kreisel, Philip A. Mudd, Angela M. Taylor, Coleen A. McNamara, Marina Cella, Sidharth V. Puram, Maxim N. Artyomov","doi":"10.1016/j.immuni.2024.08.019","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.019","url":null,"abstract":"Thymic involution is a key factor in human immune aging, leading to reduced thymic output and a decline in recent thymic emigrant (RTE) naive T cells in circulation. Currently, the precise definition of human RTEs and their corresponding cell surface markers lacks clarity. Analysis of single-cell RNA-seq/ATAC-seq data distinguished RTEs by the expression of SOX4, IKZF2, and TOX and CD38 protein, whereby surface CD38<sup>hi</sup> expression universally identified CD8<sup>+</sup> and CD4<sup>+</sup> RTEs. We further determined the dynamics of RTEs and mature cells in a cohort of 158 individuals, including age-associated transcriptional reprogramming and shifts in cytokine production. Spectral cytometry profiling revealed two axes of aging common to naive CD8<sup>+</sup> and CD4<sup>+</sup> T cells: (1) a decrease in CD38<sup>++</sup> cells (RTEs) and (2) an increase in CXCR3<sup>hi</sup> cells. Identification of RTEs enables direct assessment of thymic health. Furthermore, resolving the dynamics of naive T cell remodeling yields insight into vaccination and infection responsiveness throughout aging.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"21 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313576","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 liver macrophage population comprises resident Kupffer cells (KCs) and monocyte-derived macrophages with distinct pro- or anti-inflammatory properties that affect the severity and course of liver diseases. The mechanisms underlying macrophage differentiation and functions in metabolic dysfunction-associated steatotic liver disease and/or steatohepatitis (MASLD/MASH) remain mostly unknown. Using single-cell RNA sequencing (scRNA-seq) and fate mapping of hepatic macrophage subpopulations, we unraveled the temporal and spatial dynamics of distinct monocyte and monocyte-derived macrophage subsets in MASH. We revealed a crucial role for the Notch-Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) signaling pathway in controlling the monocyte-to-macrophage transition, with Rbpj deficiency blunting inflammatory macrophages and monocyte-derived KC differentiation and conversely promoting the emergence of protective Ly6Clo monocytes. Mechanistically, Rbpj deficiency promoted lipid uptake driven by elevated CD36 expression in Ly6Clo monocytes, enhancing their protective interactions with endothelial cells. Our findings uncover the crucial role of Notch-RBPJ signaling in monocyte-to-macrophage transition and will aid in the design of therapeutic strategies for MASH treatment.
{"title":"Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease","authors":"Wei Guo, Ziyi Li, Gerasimos Anagnostopoulos, Wan Ting Kong, Shuangyan Zhang, Svetoslav Chakarov, Amanda Shin, Jiawen Qian, Yiwen Zhu, Wenjuan Bai, Olivier Cexus, Bin'en Nie, Jing Wang, Xiaoyu Hu, Camille Blériot, Zhaoyuan Liu, Baiyong Shen, Nicolas Venteclef, Bing Su, Florent Ginhoux","doi":"10.1016/j.immuni.2024.08.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.016","url":null,"abstract":"The liver macrophage population comprises resident Kupffer cells (KCs) and monocyte-derived macrophages with distinct pro- or anti-inflammatory properties that affect the severity and course of liver diseases. The mechanisms underlying macrophage differentiation and functions in metabolic dysfunction-associated steatotic liver disease and/or steatohepatitis (MASLD/MASH) remain mostly unknown. Using single-cell RNA sequencing (scRNA-seq) and fate mapping of hepatic macrophage subpopulations, we unraveled the temporal and spatial dynamics of distinct monocyte and monocyte-derived macrophage subsets in MASH. We revealed a crucial role for the Notch-Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) signaling pathway in controlling the monocyte-to-macrophage transition, with <em>Rbpj</em> deficiency blunting inflammatory macrophages and monocyte-derived KC differentiation and conversely promoting the emergence of protective Ly6C<sup>lo</sup> monocytes. Mechanistically, <em>Rbpj</em> deficiency promoted lipid uptake driven by elevated CD36 expression in Ly6C<sup>lo</sup> monocytes, enhancing their protective interactions with endothelial cells. Our findings uncover the crucial role of Notch-RBPJ signaling in monocyte-to-macrophage transition and will aid in the design of therapeutic strategies for MASH treatment.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"12 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276839","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 : 2024-09-20DOI: 10.1016/j.immuni.2024.08.017
Alexandra R. Dvorscek, Craig I. McKenzie, Vera C. Stäheli, Zhoujie Ding, Jacqueline White, Stewart A. Fabb, Leonard Lim, Kristy O’Donnell, Catherine Pitt, Daniel Christ, Danika L. Hill, Colin W. Pouton, Deborah L. Burnett, Robert Brink, Marcus J. Robinson, David M. Tarlinton, Isaak Quast
Existing antibodies (Abs) have varied effects on humoral immunity during subsequent infections. Here, we leveraged in vivo systems that allow precise control of antigen-specific Abs and B cells to examine the impact of Ab dose, affinity, and specificity in directing B cell activation and differentiation. Abs competing with the B cell receptor (BCR) epitope showed affinity-dependent suppression. By contrast, Abs targeting a complementary epitope, not overlapping with the BCR, shifted B cell differentiation toward Ab-secreting cells. Such Abs allowed for potent germinal center (GC) responses to otherwise poorly immunogenic sites by promoting antigen capture and presentation by low-affinity B cells. These mechanisms jointly diversified the B cell repertoire by facilitating the recruitment of high- and low-affinity B cells into Ab-secreting cell, GC, and memory B cell fates. Incorporation of small amounts of monoclonal Abs into protein- or mRNA-based vaccines enhanced immunogenicity and facilitated sustained immune responses, with implications for vaccine design and our understanding of protective immunity.
现有的抗体(Abs)在随后的感染过程中对体液免疫有不同的影响。在这里,我们利用可精确控制抗原特异性抗体和 B 细胞的体内系统,研究了抗体剂量、亲和力和特异性在引导 B 细胞活化和分化方面的影响。与 B 细胞受体 (BCR) 表位竞争的抗体表现出亲和力依赖性抑制。与此相反,以互补表位为靶点、不与BCR重叠的Abs能使B细胞向分泌Abs的细胞分化。通过促进低亲和力 B 细胞对抗原的捕获和呈递,这种抗体能对免疫原性较差的部位产生有效的生殖中心(GC)反应。这些机制通过促进高亲和力和低亲和力 B 细胞招募成为抗体分泌细胞、GC 和记忆 B 细胞,共同实现了 B 细胞谱系的多样化。在基于蛋白质或 mRNA 的疫苗中加入少量单克隆抗体可增强免疫原性并促进持续的免疫应答,这对疫苗设计和我们对保护性免疫的理解都有影响。
{"title":"Conversion of vaccines from low to high immunogenicity by antibodies with epitope complementarity","authors":"Alexandra R. Dvorscek, Craig I. McKenzie, Vera C. Stäheli, Zhoujie Ding, Jacqueline White, Stewart A. Fabb, Leonard Lim, Kristy O’Donnell, Catherine Pitt, Daniel Christ, Danika L. Hill, Colin W. Pouton, Deborah L. Burnett, Robert Brink, Marcus J. Robinson, David M. Tarlinton, Isaak Quast","doi":"10.1016/j.immuni.2024.08.017","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.017","url":null,"abstract":"<p>Existing antibodies (Abs) have varied effects on humoral immunity during subsequent infections. Here, we leveraged <em>in vivo</em> systems that allow precise control of antigen-specific Abs and B cells to examine the impact of Ab dose, affinity, and specificity in directing B cell activation and differentiation. Abs competing with the B cell receptor (BCR) epitope showed affinity-dependent suppression. By contrast, Abs targeting a complementary epitope, not overlapping with the BCR, shifted B cell differentiation toward Ab-secreting cells. Such Abs allowed for potent germinal center (GC) responses to otherwise poorly immunogenic sites by promoting antigen capture and presentation by low-affinity B cells. These mechanisms jointly diversified the B cell repertoire by facilitating the recruitment of high- and low-affinity B cells into Ab-secreting cell, GC, and memory B cell fates. Incorporation of small amounts of monoclonal Abs into protein- or mRNA-based vaccines enhanced immunogenicity and facilitated sustained immune responses, with implications for vaccine design and our understanding of protective immunity.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"196 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246739","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 : 2024-09-19DOI: 10.1016/j.immuni.2024.09.009
Richard A. Flavell, Esen Sefik
Insight into how the immune system recognizes and responds to pathogens had led to landmark advances in biology and medicine in the last decades. This year’s Albert Lasker Award for Basic Medical Research honors Zhijian “James” Chen for the discovery of cGAS, the enzyme that senses foreign and “pathogenic” self-DNA—self-DNA aberrantly located in intracellular compartments. The definition of the cGAS-STING pathway opens new horizons for the understanding and treatment of human disease.
{"title":"Sensing DNA as danger: The discovery of cGAS","authors":"Richard A. Flavell, Esen Sefik","doi":"10.1016/j.immuni.2024.09.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.009","url":null,"abstract":"<p>Insight into how the immune system recognizes and responds to pathogens had led to landmark advances in biology and medicine in the last decades. This year’s Albert Lasker Award for Basic Medical Research honors Zhijian “James” Chen for the discovery of cGAS, the enzyme that senses foreign and “pathogenic” self-DNA—self-DNA aberrantly located in intracellular compartments. The definition of the cGAS-STING pathway opens new horizons for the understanding and treatment of human disease.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"50 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246102","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 : 2024-09-18DOI: 10.1016/j.immuni.2024.08.013
Samantha Y. Tse-Kang, Khursheed A. Wani, Nicholas D. Peterson, Amanda Page, Fiachra Humphries, Read Pukkila-Worley
Toll/interleukin-1/resistance (TIR)-domain proteins with enzymatic activity are essential for immunity in plants, animals, and bacteria. However, it is not known how these proteins function in pathogen sensing in animals. We discovered that the lone enzymatic TIR-domain protein in the nematode C. elegans (TIR-1, homolog of mammalian sterile alpha and TIR motif-containing 1 [SARM1]) was strategically expressed on the membranes of a specific intracellular compartment called lysosome-related organelles. The positioning of TIR-1 on lysosome-related organelles enables intestinal epithelial cells in the nematode C. elegans to survey for pathogen effector-triggered host damage. A virulence effector secreted by the bacterial pathogen Pseudomonas aeruginosa alkalinized and condensed lysosome-related organelles. This pathogen-induced morphological change in lysosome-related organelles triggered TIR-1 multimerization, which engaged its intrinsic NAD+ hydrolase (NADase) activity to activate the p38 innate immune pathway and protect the host against microbial intoxication. Thus, TIR-1 is a guard protein in an effector-triggered immune response, which enables intestinal epithelial cells to survey for pathogen-induced host damage.
{"title":"Intestinal immunity in C. elegans is activated by pathogen effector-triggered aggregation of the guard protein TIR-1 on lysosome-related organelles","authors":"Samantha Y. Tse-Kang, Khursheed A. Wani, Nicholas D. Peterson, Amanda Page, Fiachra Humphries, Read Pukkila-Worley","doi":"10.1016/j.immuni.2024.08.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.013","url":null,"abstract":"<p>Toll/interleukin-1/resistance (TIR)-domain proteins with enzymatic activity are essential for immunity in plants, animals, and bacteria. However, it is not known how these proteins function in pathogen sensing in animals. We discovered that the lone enzymatic TIR-domain protein in the nematode <em>C. elegans</em> (TIR-1, homolog of mammalian sterile alpha and TIR motif-containing 1 [SARM1]) was strategically expressed on the membranes of a specific intracellular compartment called lysosome-related organelles. The positioning of TIR-1 on lysosome-related organelles enables intestinal epithelial cells in the nematode <em>C. elegans</em> to survey for pathogen effector-triggered host damage. A virulence effector secreted by the bacterial pathogen <em>Pseudomonas aeruginosa</em> alkalinized and condensed lysosome-related organelles. This pathogen-induced morphological change in lysosome-related organelles triggered TIR-1 multimerization, which engaged its intrinsic NAD<sup>+</sup> hydrolase (NADase) activity to activate the p38 innate immune pathway and protect the host against microbial intoxication. Thus, TIR-1 is a guard protein in an effector-triggered immune response, which enables intestinal epithelial cells to survey for pathogen-induced host damage.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"33 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142237023","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 : 2024-09-13DOI: 10.1016/j.immuni.2024.08.014
Johanna Chiffelle, David Barras, Rémy Pétremand, Angela Orcurto, Sara Bobisse, Marion Arnaud, Aymeric Auger, Blanca Navarro Rodrigo, Eleonora Ghisoni, Christophe Sauvage, Damien Saugy, Alexandra Michel, Baptiste Murgues, Noémie Fahr, Martina Imbimbo, Maria Ochoa de Olza, Sofiya Latifyan, Isaac Crespo, Fabrizio Benedetti, Raphael Genolet, George Coukos
Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.
{"title":"Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma","authors":"Johanna Chiffelle, David Barras, Rémy Pétremand, Angela Orcurto, Sara Bobisse, Marion Arnaud, Aymeric Auger, Blanca Navarro Rodrigo, Eleonora Ghisoni, Christophe Sauvage, Damien Saugy, Alexandra Michel, Baptiste Murgues, Noémie Fahr, Martina Imbimbo, Maria Ochoa de Olza, Sofiya Latifyan, Isaac Crespo, Fabrizio Benedetti, Raphael Genolet, George Coukos","doi":"10.1016/j.immuni.2024.08.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.014","url":null,"abstract":"<p>Adoptive cell therapy (ACT) using <em>in vitro</em> expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon <em>in vitro</em> expansion, yielding products enriched in tumor-specific CD8<sup>+</sup> cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"3 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211518","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 : 2024-09-10DOI: 10.1016/j.immuni.2024.08.012
Giuseppe Giuliani, Jayajit Das
Intestinal macrophages play a key role in regulating immune tolerance in the gut. In this issue of Immunity, Mertens et al. uncover a mechanism for the establishment of memory in macrophage tolerance in the gut involving a bistable metabolic switch in macrophages and an intercellular positive feedback between macrophages and intestinal epithelial cells (IECs).
{"title":"Neighbor’s feedback helps macrophages learn tolerance in the gut","authors":"Giuseppe Giuliani, Jayajit Das","doi":"10.1016/j.immuni.2024.08.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.08.012","url":null,"abstract":"<p>Intestinal macrophages play a key role in regulating immune tolerance in the gut. In this issue of <em>Immunity</em>, Mertens et al. uncover a mechanism for the establishment of memory in macrophage tolerance in the gut involving a bistable metabolic switch in macrophages and an intercellular positive feedback between macrophages and intestinal epithelial cells (IECs).</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"108 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142161038","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}