Pub Date : 2024-07-23DOI: 10.1016/j.immuni.2024.06.015
Tissue adaptation is required for regulatory T (Treg) cell function within organs. Whether this program shares aspects with other tissue-localized immune populations is unclear. Here, we analyzed single-cell chromatin accessibility data, including the transposable element (TE) landscape of CD45+ immune cells from colon, skin, adipose tissue, and spleen. We identified features of organ-specific tissue adaptation across different immune cells. Focusing on tissue Treg cells, we found conservation of the Treg tissue adaptation program in other tissue-localized immune cells, such as amphiregulin-producing T helper (Th)17 cells. Accessible TEs can act as regulatory elements, but their contribution to tissue adaptation is not understood. TE landscape analysis revealed an enrichment of specific transcription factor binding motifs in TE regions within accessible chromatin peaks. TEs, specifically from the LTR family, were located in enhancer regions and associated with tissue adaptation. These findings broaden our understanding of immune tissue residency and provide an important step toward organ-specific immune interventions.
{"title":"Single-cell chromatin accessibility and transposable element landscapes reveal shared features of tissue-residing immune cells","authors":"","doi":"10.1016/j.immuni.2024.06.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.015","url":null,"abstract":"<p>Tissue adaptation is required for regulatory T (Treg) cell function within organs. Whether this program shares aspects with other tissue-localized immune populations is unclear. Here, we analyzed single-cell chromatin accessibility data, including the transposable element (TE) landscape of CD45<sup>+</sup> immune cells from colon, skin, adipose tissue, and spleen. We identified features of organ-specific tissue adaptation across different immune cells. Focusing on tissue Treg cells, we found conservation of the Treg tissue adaptation program in other tissue-localized immune cells, such as amphiregulin-producing T helper (Th)17 cells. Accessible TEs can act as regulatory elements, but their contribution to tissue adaptation is not understood. TE landscape analysis revealed an enrichment of specific transcription factor binding motifs in TE regions within accessible chromatin peaks. TEs, specifically from the LTR family, were located in enhancer regions and associated with tissue adaptation. These findings broaden our understanding of immune tissue residency and provide an important step toward organ-specific immune interventions.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754583","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 : 2024-07-22DOI: 10.1016/j.immuni.2024.06.016
Lung-tissue-resident memory (TRM) CD8+ T cells are critical for heterosubtypic immunity against influenza virus (IAV) reinfection. How TRM cells surveil the lung, respond to infection, and interact with other cells remains unresolved. Here, we used IAV infection of mice in combination with intravital and static imaging to define the spatiotemporal dynamics of lung TRM cells before and after recall infection. CD69+CD103+ TRM cells preferentially localized to lung sites of prior IAV infection, where they exhibited patrolling behavior. After rechallenge, lung TRM cells formed tight clusters in an antigen-dependent manner. Transcriptomic analysis of IAV-specific TRM cells revealed the expression of several factors that regulate myeloid cell biology. In vivo rechallenge experiments demonstrated that protection elicited by TRM cells is orchestrated in part by interferon (IFN)-γ-mediated recruitment of inflammatory monocytes into the lungs. Overall, these data illustrate the dynamic landscapes of CD103+ lung TRM cells that mediate early protective immunity against IAV infection.
{"title":"Dynamic landscapes and protective immunity coordinated by influenza-specific lung-resident memory CD8+ T cells revealed by intravital imaging","authors":"","doi":"10.1016/j.immuni.2024.06.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.016","url":null,"abstract":"<p>Lung-tissue-resident memory (T<sub>RM</sub>) CD8<sup>+</sup> T cells are critical for heterosubtypic immunity against influenza virus (IAV) reinfection. How T<sub>RM</sub> cells surveil the lung, respond to infection, and interact with other cells remains unresolved. Here, we used IAV infection of mice in combination with intravital and static imaging to define the spatiotemporal dynamics of lung T<sub>RM</sub> cells before and after recall infection. CD69<sup>+</sup>CD103<sup>+</sup> T<sub>RM</sub> cells preferentially localized to lung sites of prior IAV infection, where they exhibited patrolling behavior. After rechallenge, lung T<sub>RM</sub> cells formed tight clusters in an antigen-dependent manner. Transcriptomic analysis of IAV-specific T<sub>RM</sub> cells revealed the expression of several factors that regulate myeloid cell biology. <em>In vivo</em> rechallenge experiments demonstrated that protection elicited by T<sub>RM</sub> cells is orchestrated in part by interferon (IFN)-γ-mediated recruitment of inflammatory monocytes into the lungs. Overall, these data illustrate the dynamic landscapes of CD103<sup>+</sup> lung T<sub>RM</sub> cells that mediate early protective immunity against IAV infection.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141746538","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 : 2024-07-22DOI: 10.1016/j.immuni.2024.06.014
The memory CD8+ T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8+ T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of TRM cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to TRM cells across organs. Finally, we found that although terminal TEX cells share accessible regulatory elements with TRM cells, they are defined by TEX-specific epigenetic features absent from TRM cells. Together, this comprehensive data resource shows that TRM cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.
记忆性 CD8+ T 细胞池包含表型和转录异质性亚群,具有专门的功能和再循环模式。在这里,我们研究了在四种不同的感染模型中从七个非淋巴器官中分离出来的 CD8+ T 细胞的表观遗传学景观,以及它们的循环 T 细胞对应物。利用单细胞转座酶可获取染色质测序(scATAC-seq),我们发现组织驻留记忆T细胞(TRM)和循环记忆T细胞(TCIRC)沿着不同的表观遗传学轨迹发展。我们确定了TRM细胞发育的器官特异性转录调控因子,包括FOSB、FOS、FOSL1和BACH2,并定义了各器官TRM细胞共有的表观遗传学特征。最后,我们发现尽管末端TEX细胞与TRM细胞共享可访问的调控元件,但它们是由TRM细胞所没有的TEX特异性表观遗传特征所定义的。总之,这一全面的数据资源表明,TRM 细胞的发育伴随着动态转录组的改变和染色质可及性的改变,这些改变引导着组织适应性和功能上不同的 T 细胞状态。
{"title":"Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation","authors":"","doi":"10.1016/j.immuni.2024.06.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.014","url":null,"abstract":"<p>The memory CD8<sup>+</sup> T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8<sup>+</sup> T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (T<sub>RM</sub>) cells and circulating memory T (T<sub>CIRC</sub>) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of T<sub>RM</sub> cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to T<sub>RM</sub> cells across organs. Finally, we found that although terminal T<sub>EX</sub> cells share accessible regulatory elements with T<sub>RM</sub> cells, they are defined by T<sub>EX</sub>-specific epigenetic features absent from T<sub>RM</sub> cells. Together, this comprehensive data resource shows that T<sub>RM</sub> cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141746537","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 : 2024-07-15DOI: 10.1016/j.immuni.2024.06.013
Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus’s glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines.
{"title":"Deep mutational scanning reveals functional constraints and antibody-escape potential of Lassa virus glycoprotein complex","authors":"","doi":"10.1016/j.immuni.2024.06.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.013","url":null,"abstract":"<p>Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, <em>Mastomys</em> rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus’s glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618435","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 : 2024-07-15DOI: 10.1016/j.immuni.2024.06.010
Antibiotic use in early life disrupts microbial colonization and increases the risk of developing allergies and asthma. We report that mice given antibiotics in early life (EL-Abx), but not in adulthood, were more susceptible to house dust mite (HDM)-induced allergic airway inflammation. This susceptibility was maintained even after normalization of the gut microbiome. EL-Abx decreased systemic levels of indole-3-propionic acid (IPA), which induced long-term changes to cellular stress, metabolism, and mitochondrial respiration in the lung epithelium. IPA reduced mitochondrial respiration and superoxide production and altered chemokine and cytokine production. Consequently, early-life IPA supplementation protected EL-Abx mice against exacerbated HDM-induced allergic airway inflammation in adulthood. These results reveal a mechanism through which EL-Abx can predispose the lung to allergic airway inflammation and highlight a possible preventative approach to mitigate the detrimental consequences of EL-Abx.
{"title":"Antibiotic-driven dysbiosis in early life disrupts indole-3-propionic acid production and exacerbates allergic airway inflammation in adulthood","authors":"","doi":"10.1016/j.immuni.2024.06.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.010","url":null,"abstract":"<p>Antibiotic use in early life disrupts microbial colonization and increases the risk of developing allergies and asthma. We report that mice given antibiotics in early life (EL-Abx), but not in adulthood, were more susceptible to house dust mite (HDM)-induced allergic airway inflammation. This susceptibility was maintained even after normalization of the gut microbiome. EL-Abx decreased systemic levels of indole-3-propionic acid (IPA), which induced long-term changes to cellular stress, metabolism, and mitochondrial respiration in the lung epithelium. IPA reduced mitochondrial respiration and superoxide production and altered chemokine and cytokine production. Consequently, early-life IPA supplementation protected EL-Abx mice against exacerbated HDM-induced allergic airway inflammation in adulthood. These results reveal a mechanism through which EL-Abx can predispose the lung to allergic airway inflammation and highlight a possible preventative approach to mitigate the detrimental consequences of EL-Abx.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618436","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}
Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA1, like that of the phospholipase PLA2G3, the prostaglandin D2 (PGD2) synthase L-PGDS, or the PGD2 receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA1 then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD2 generation, and feedforward ATX-LPA1 amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA1 agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation.
肥大细胞(MC)与成纤维细胞的相互作用是MC在组织微环境中成熟的必要条件,但其基本机制尚不完全清楚。通过对30个缺乏脂质相关基因的小鼠品系进行表型筛选,我们发现溶血磷脂酸(LPA)受体LPA1的缺失与磷脂酶PLA2G3、前列腺素D2(PGD2)合成酶L-PGDS或PGD2受体DP1的缺失一样,都会影响MC的成熟,从而导致过敏性休克。从机制上讲,MC 分泌的 PLA2G3 作用于细胞外囊泡 (EV),以提供溶血磷脂,溶血磷脂在成纤维细胞衍生的自旋素 (ATX) 作用下转化为 LPA。成纤维细胞 LPA1 随后通过促进整合素介导的 MC-成纤维细胞粘附、IL-33-ST2 信号传导、L-PGDS 驱动的 PGD2 生成以及 ATX-LPA1 的前馈放大,整合 MC 成熟所需的多种途径。补充 LPA1 激动剂或 PLA2G3 修饰的 EV 可恢复 PLA2G3 缺乏导致的 MC 成熟缺陷。因此,PLA2G3驱动的溶血磷脂、二十碳六烷酸、整合素和细胞因子信号的脂质协调旁分泌回路可微调MC与成纤维细胞之间的交流,从而确保MC的成熟。
{"title":"Lipid-orchestrated paracrine circuit coordinates mast cell maturation and anaphylaxis through functional interaction with fibroblasts","authors":"Yoshitaka Taketomi, Takayoshi Higashi, Kuniyuki Kano, Yoshimi Miki, Chika Mochizuki, Shota Toyoshima, Yoshimichi Okayama, Yasumasa Nishito, Susumu Nakae, Satoshi Tanaka, Suzumi M. Tokuoka, Yoshiya Oda, Shigeyuki Shichino, Satoshi Ueha, Kouji Matsushima, Noriyuki Akahoshi, Satoshi Ishii, Jerold Chun, Junken Aoki, Makoto Murakami","doi":"10.1016/j.immuni.2024.06.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.012","url":null,"abstract":"<p>Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA<sub>1</sub>, like that of the phospholipase PLA2G3, the prostaglandin D<sub>2</sub> (PGD<sub>2</sub>) synthase L-PGDS, or the PGD<sub>2</sub> receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA<sub>1</sub> then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD<sub>2</sub> generation, and feedforward ATX-LPA<sub>1</sub> amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA<sub>1</sub> agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597351","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 : 2024-07-09Epub Date: 2024-06-14DOI: 10.1016/j.immuni.2024.05.017
Barney Viengkhou, Emina Hayashida, Sarah McGlasson, Katie Emelianova, Deborah Forbes, Stewart Wiseman, Joanna Wardlaw, Rovin Verdillo, Sarosh R Irani, Darragh Duffy, Fredrik Piehl, Lipin Loo, Axel Pagenstecher, G Greg Neely, Yanick J Crow, Iain L Campbell, David P J Hunt, Markus J Hofer
Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.
{"title":"The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies.","authors":"Barney Viengkhou, Emina Hayashida, Sarah McGlasson, Katie Emelianova, Deborah Forbes, Stewart Wiseman, Joanna Wardlaw, Rovin Verdillo, Sarosh R Irani, Darragh Duffy, Fredrik Piehl, Lipin Loo, Axel Pagenstecher, G Greg Neely, Yanick J Crow, Iain L Campbell, David P J Hunt, Markus J Hofer","doi":"10.1016/j.immuni.2024.05.017","DOIUrl":"10.1016/j.immuni.2024.05.017","url":null,"abstract":"<p><p>Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":25.5,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327470","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 : 2024-07-09DOI: 10.1016/j.immuni.2024.06.006
Danielle M. Clancy, Julie Andries, Savvas N. Savvides
Interleukin-1 (IL-1) family cytokines are key immunological regulators that achieve their signaling prowess after post-translational proteolytic processing. In this issue of Immunity, Dong et al. reveal the structural consequences of this process on proinflammatory IL-18, demonstrating that pro-IL-18 and mature IL-18 are structurally distinct.
{"title":"The pros and confs of IL-18 activation","authors":"Danielle M. Clancy, Julie Andries, Savvas N. Savvides","doi":"10.1016/j.immuni.2024.06.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.006","url":null,"abstract":"<p>Interleukin-1 (IL-1) family cytokines are key immunological regulators that achieve their signaling prowess after post-translational proteolytic processing. In this issue of <em>Immunity</em>, Dong et al. reveal the structural consequences of this process on proinflammatory IL-18, demonstrating that pro-IL-18 and mature IL-18 are structurally distinct.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561722","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 : 2024-07-09DOI: 10.1016/j.immuni.2024.05.020
Laurent Abel, Jean-Laurent Casanova
Regardless of microbial virulence (i.e., the global infection-fatality ratio), age generally drives the prevalence of death from infection in unvaccinated humans. Four mortality patterns are recognized: the common U- and L-shaped curves of endemic infections and the unique W- and J-shaped curves of pandemic infections. We suggest that these patterns result from different sets of human genetic and immunological determinants. In this model, it is the interplay between (1) monogenic genotypes affecting immunity to primary infection that preferentially manifest early in life and related genotypes or their phenocopies, including auto-antibodies, which manifest later in life and (2) the occurrence and persistence of adaptive, acquired immunity to primary or cross-reactive infections, which shapes the age-dependent pattern of human deaths from infection.
无论微生物的毒力(即全球感染-死亡比率)如何,年龄通常会影响未接种疫苗的人类因感染而死亡的流行率。目前已发现四种死亡模式:流行性感染常见的 U 型和 L 型曲线,以及大流行性感染特有的 W 型和 J 型曲线。我们认为,这些模式是由不同的人类基因和免疫决定因素造成的。在这一模式中,(1) 影响原发性感染免疫力的单基因型在生命早期优先显现,相关基因型或其表型(包括自身抗体)在生命晚期显现,(2) 对原发性感染或交叉反应感染的适应性获得性免疫的发生和持续,这两者之间的相互作用形成了人类死于感染的年龄依赖模式。
{"title":"Human determinants of age-dependent patterns of death from infection","authors":"Laurent Abel, Jean-Laurent Casanova","doi":"10.1016/j.immuni.2024.05.020","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.05.020","url":null,"abstract":"<p>Regardless of microbial virulence (i.e., the global infection-fatality ratio), age generally drives the prevalence of death from infection in unvaccinated humans. Four mortality patterns are recognized: the common U- and L-shaped curves of endemic infections and the unique W- and J-shaped curves of pandemic infections. We suggest that these patterns result from different sets of human genetic and immunological determinants. In this model, it is the interplay between (1) monogenic genotypes affecting immunity to primary infection that preferentially manifest early in life and related genotypes or their phenocopies, including auto-antibodies, which manifest later in life and (2) the occurrence and persistence of adaptive, acquired immunity to primary or cross-reactive infections, which shapes the age-dependent pattern of human deaths from infection.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561767","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 : 2024-07-09Epub Date: 2024-05-21DOI: 10.1016/j.immuni.2024.04.027
Joseph Jorssen, Glenn Van Hulst, Kiréna Mollers, Julien Pujol, Georgios Petrellis, Antonio P Baptista, Sjoerd Schetters, Frédéric Baron, Jo Caers, Bart N Lambrecht, Benjamin G Dewals, Fabrice Bureau, Christophe J Desmet
The activities, ontogeny, and mechanisms of lineage expansion of eosinophils are less well resolved than those of other immune cells, despite the use of biological therapies targeting the eosinophilia-promoting cytokine interleukin (IL)-5 or its receptor, IL-5Rα. We combined single-cell proteomics and transcriptomics and generated transgenic IL-5Rα reporter mice to revisit eosinophilopoiesis. We reconciled human and murine eosinophilopoiesis and provided extensive cell-surface immunophenotyping and transcriptomes at different stages along the continuum of eosinophil maturation. We used these resources to show that IL-5 promoted eosinophil-lineage expansion via transit amplification, while its deletion or neutralization did not compromise eosinophil maturation. Informed from our resources, we also showed that interferon response factor-8, considered an essential promoter of myelopoiesis, was not intrinsically required for eosinophilopoiesis. This work hence provides resources, methods, and insights for understanding eosinophil ontogeny, the effects of current precision therapeutics, and the regulation of eosinophil development and numbers in health and disease.
{"title":"Single-cell proteomics and transcriptomics capture eosinophil development and identify the role of IL-5 in their lineage transit amplification.","authors":"Joseph Jorssen, Glenn Van Hulst, Kiréna Mollers, Julien Pujol, Georgios Petrellis, Antonio P Baptista, Sjoerd Schetters, Frédéric Baron, Jo Caers, Bart N Lambrecht, Benjamin G Dewals, Fabrice Bureau, Christophe J Desmet","doi":"10.1016/j.immuni.2024.04.027","DOIUrl":"10.1016/j.immuni.2024.04.027","url":null,"abstract":"<p><p>The activities, ontogeny, and mechanisms of lineage expansion of eosinophils are less well resolved than those of other immune cells, despite the use of biological therapies targeting the eosinophilia-promoting cytokine interleukin (IL)-5 or its receptor, IL-5Rα. We combined single-cell proteomics and transcriptomics and generated transgenic IL-5Rα reporter mice to revisit eosinophilopoiesis. We reconciled human and murine eosinophilopoiesis and provided extensive cell-surface immunophenotyping and transcriptomes at different stages along the continuum of eosinophil maturation. We used these resources to show that IL-5 promoted eosinophil-lineage expansion via transit amplification, while its deletion or neutralization did not compromise eosinophil maturation. Informed from our resources, we also showed that interferon response factor-8, considered an essential promoter of myelopoiesis, was not intrinsically required for eosinophilopoiesis. This work hence provides resources, methods, and insights for understanding eosinophil ontogeny, the effects of current precision therapeutics, and the regulation of eosinophil development and numbers in health and disease.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":25.5,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081270","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}