Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.07.006
Huijuan Le , Yanyan Wang , Jiefei Zhou , Dan Li , Zizhen Gong , Fangxinxing Zhu , Jian Wang , Chunyan Tian , Wei Cai , Jin Wu
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in preterm infants and the most common cause of neonatal death, whereas the molecular mechanism of intestinal injury remains unclear accompanied by deficiency of effective therapeutic approaches. GIT2 (G-protein-coupled receptor kinase interacting proteins 2) can affect innate and adaptive immunity and has been involved in multiple inflammatory disorders. In this study, we investigated whether GIT2 participates in the pathogenesis of NEC. Here we found that intestinal Git2 gene expression was significantly increased in NEC patients and NEC mice, which positively correlated with the tissue damage severity, and Git2 deficiency could potently protect against NEC development in mice. Mechanistically, Git2 gene knockout dramatically increased the recruitment of MDSCs in the intestine, and in vivo depletion of MDSCs almost completely abrogated the protective effect of Git2 deficiency on NEC. Moreover, Git2 deficiency induced MDSCs intestinal accumulation mainly relied on CXCL1/CXCL12 signaling, as evidenced by the significant increment of CXCL1 and CXCL12 levels in intestinal epithelium of Git2-/- mice and dramatically decrease of MDSCs accumulation in intestine as well as increase of NEC severity upon treatment of CXCL1/CXCL12 pathway inhibitors. In addition, Git2 deficiency induced up-regulation of CXCL1 and CXCL12 is at least partially mediated through activating NF-κB signaling. Thus, our findings suggest that GIT2 is involved in the pathogenesis of NEC, and targeting GIT2 may be a potential preventive and therapeutic approach for NEC.
坏死性小肠结肠炎（NEC）是早产儿的一种严重胃肠道疾病，也是新生儿死亡的最常见原因，但肠道损伤的分子机制仍不清楚，也缺乏有效的治疗方法。GIT2（G-蛋白偶联受体激酶相互作用蛋白 2）可影响先天性免疫和适应性免疫，并参与多种炎症性疾病。本研究探讨了 GIT2 是否参与了 NEC 的发病机制。我们发现，肠道 Git2 基因在 NEC 患者和 NEC 小鼠中的表达明显增加，与组织损伤的严重程度呈正相关，Git2 基因缺失可有效防止小鼠 NEC 的发生。从机理上讲，Git2 基因敲除可显著增加肠道内 MDSCs 的募集，而体内 MDSCs 的耗竭几乎完全减弱了 Git2 缺乏对 NEC 的保护作用。此外，Git2缺陷诱导的MDSCs肠道聚集主要依赖于CXCL1/CXCL12信号转导，这表现在Git2-/-小鼠肠上皮细胞中CXCL1和CXCL12水平显著升高，CXCL1/CXCL12通路抑制剂治疗后MDSCs肠道聚集显著减少，NEC严重程度增加。此外，Git2 缺乏诱导的 CXCL1 和 CXCL12 上调至少部分是通过激活 NF-κB 信号介导的。因此，我们的研究结果表明，GIT2 参与了 NEC 的发病机制，靶向 GIT2 可能是一种潜在的 NEC 预防和治疗方法。
{"title":"Git2 deficiency promotes MDSCs recruitment in intestine via NF-κB-CXCL1/CXCL12 pathway and ameliorates necrotizing enterocolitis","authors":"Huijuan Le , Yanyan Wang , Jiefei Zhou , Dan Li , Zizhen Gong , Fangxinxing Zhu , Jian Wang , Chunyan Tian , Wei Cai , Jin Wu","doi":"10.1016/j.mucimm.2024.07.006","DOIUrl":"10.1016/j.mucimm.2024.07.006","url":null,"abstract":"<div><div>Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in preterm infants and the most common cause of neonatal death, whereas the molecular mechanism of intestinal injury remains unclear accompanied by deficiency of effective therapeutic approaches. GIT2 (G-protein-coupled receptor kinase interacting proteins 2) can affect innate and adaptive immunity and has been involved in multiple inflammatory disorders. In this study, we investigated whether GIT2 participates in the pathogenesis of NEC. Here we found that intestinal <em>Git2</em> gene expression was significantly increased in NEC patients and NEC mice, which positively correlated with the tissue damage severity, and <em>Git2</em> deficiency could potently protect against NEC development in mice. Mechanistically, <em>Git2</em> gene knockout dramatically increased the recruitment of MDSCs in the intestine, and <em>in vivo</em> depletion of MDSCs almost completely abrogated the protective effect of <em>Git2</em> deficiency on NEC. Moreover, <em>Git2</em> deficiency induced MDSCs intestinal accumulation mainly relied on CXCL1/CXCL12 signaling, as evidenced by the significant increment of CXCL1 and CXCL12 levels in intestinal epithelium of <em>Git2</em><sup>-/-</sup> mice and dramatically decrease of MDSCs accumulation in intestine as well as increase of NEC severity upon treatment of CXCL1/CXCL12 pathway inhibitors. In addition, <em>Git2</em> deficiency induced up-regulation of CXCL1 and CXCL12 is at least partially mediated through activating NF-κB signaling. Thus, our findings suggest that GIT2 is involved in the pathogenesis of NEC, and targeting GIT2 may be a potential preventive and therapeutic approach for NEC.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1060-1071"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.05.007
Mycobacterium tuberculosis (Mtb)-infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils to the lung is linked to increased bacterial burden and aggravated pathology in TB. The basis for the permissiveness of neutrophils for Mtb and the ability to be pathogenic in TB has been elusive. Here, we identified metabolic and functional features of neutrophils that contribute to their permissiveness in Mtb infection. Using single-cell metabolic and transcriptional analyses, we found that neutrophils in the Mtb-infected lung displayed elevated mitochondrial metabolism, which was largely attributed to the induction of activated neutrophils with enhanced metabolic activities. The activated neutrophil subpopulation was also identified in the lung granulomas from Mtb-infected non-human primates. Functionally, activated neutrophils harbored more viable bacteria and displayed enhanced lipid uptake and accumulation. Surprisingly, we found that interferon-γ promoted the activation of lung neutrophils during Mtb infection. Lastly, perturbation of lipid uptake pathways selectively compromised Mtb survival in activated neutrophils. These findings suggest that neutrophil heterogeneity and metabolic diversity are key to their permissiveness for Mtb and that metabolic pathways in neutrophils represent potential host-directed therapeutics in TB.
{"title":"Metabolically active neutrophils represent a permissive niche for Mycobacterium tuberculosis","authors":"","doi":"10.1016/j.mucimm.2024.05.007","DOIUrl":"10.1016/j.mucimm.2024.05.007","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (Mtb)-infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils to the lung is linked to increased bacterial burden and aggravated pathology in TB. The basis for the permissiveness of neutrophils for Mtb and the ability to be pathogenic in TB has been elusive. Here, we identified metabolic and functional features of neutrophils that contribute to their permissiveness in Mtb infection. Using single-cell metabolic and transcriptional analyses, we found that neutrophils in the Mtb-infected lung displayed elevated mitochondrial metabolism, which was largely attributed to the induction of activated neutrophils with enhanced metabolic activities. The activated neutrophil subpopulation was also identified in the lung granulomas from Mtb-infected non-human primates. Functionally, activated neutrophils harbored more viable bacteria and displayed enhanced lipid uptake and accumulation. Surprisingly, we found that interferon-γ promoted the activation of lung neutrophils during Mtb infection. Lastly, perturbation of lipid uptake pathways selectively compromised Mtb survival in activated neutrophils. These findings suggest that neutrophil heterogeneity and metabolic diversity are key to their permissiveness for Mtb and that metabolic pathways in neutrophils represent potential host-directed therapeutics in TB.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 825-842"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.06.005
The increased risk of food allergy in infants with atopic dermatitis (AD) has long been recognized; an epidemiologic phenomenon termed “the atopic march.” Current literature supports the hypothesis that food antigen exposure through the disrupted skin barrier in AD leads to food antigen-specific immunoglobulin E production and food sensitization. However, there is growing evidence that inflammation in the skin drives intestinal remodeling via circulating inflammatory signals, microbiome alterations, metabolites, and the nervous system. We explore how this skin-gut axis helps to explain the link between AD and food allergy beyond sensitization.
{"title":"Atopic dermatitis and food allergy: More than sensitization","authors":"","doi":"10.1016/j.mucimm.2024.06.005","DOIUrl":"10.1016/j.mucimm.2024.06.005","url":null,"abstract":"<div><div>The increased risk of food allergy in infants with atopic dermatitis (AD) has long been recognized; an epidemiologic phenomenon termed “the atopic march.” Current literature supports the hypothesis that food antigen exposure through the disrupted skin barrier in AD leads to food antigen-specific immunoglobulin E production and food sensitization. However, there is growing evidence that inflammation in the skin drives intestinal remodeling via circulating inflammatory signals, microbiome alterations, metabolites, and the nervous system. We explore how this skin-gut axis helps to explain the link between AD and food allergy beyond sensitization.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1128-1140"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.06.007
Regulatory T cells (Tregs) are well-known to mediate peripheral tolerance at homeostasis, and there is a growing appreciation for their role in modulating infectious disease immunity. Following acute and chronic infections, Tregs can restrict pathogen-specific T cell responses to limit immunopathology. However, it is unclear if Tregs mediate control of pathology and immunity in distal tissue sites during localized infections. We investigated the role of Tregs in immunity and disease in various tissue compartments in the context of “mild” vaginal Zika virus infection. We found that Tregs are critical to generating robust virus-specific CD8 T cell responses in the initial infection site. Further, Tregs limit inflammatory cytokines and immunopathology during localized infection; a dysregulated immune response in Treg-depleted mice leads to increased T cell infiltrates and immunopathology in both the vagina and the central nervous system (CNS). Importantly, these CNS infiltrates are not present at the same magnitude during infection of Treg-sufficient mice, in which there is no CNS immunopathology. Our data suggest that Tregs are necessary to generate a robust virus-specific response at the mucosal site of infection, while Treg-mediated restriction of bystander inflammation limits immunopathology both at the site of infection as well as distal tissue sites.
众所周知，调节性 T 细胞（Treg）在平衡状态下介导外周耐受性，而人们也越来越认识到它们在调节传染病免疫方面的作用。急性和慢性感染后，调节性 T 细胞可限制病原体特异性 T 细胞反应，从而限制免疫病理学。然而，目前还不清楚在局部感染期间，Tregs 是否能介导对远端组织部位病理和免疫的控制。我们以 "轻度 "阴道寨卡病毒（ZIKV）感染为背景，研究了Tregs在不同组织区免疫和疾病中的作用。我们发现，Tregs 对于在初始感染部位产生强大的病毒特异性 CD8 T 细胞反应至关重要。此外，Tregs 还能限制局部感染期间的炎性细胞因子和免疫病理；Treg 缺失的小鼠免疫反应失调会导致阴道和中枢神经系统（CNS）的 T 细胞浸润和免疫病理增加。重要的是，这些中枢神经系统浸润在感染 Treg 充足的小鼠时不会以同样的程度出现，因为在这种情况下不会出现中枢神经系统免疫病理。我们的数据表明，Tregs 是在粘膜感染部位产生强大的病毒特异性反应的必要条件，而 Treg 介导的旁观者炎症限制了感染部位和远端组织部位的免疫病理。
{"title":"Regulatory T cells restrict immunity and pathology in distal tissue sites following a localized infection","authors":"","doi":"10.1016/j.mucimm.2024.06.007","DOIUrl":"10.1016/j.mucimm.2024.06.007","url":null,"abstract":"<div><div>Regulatory T cells (Tregs) are well-known to mediate peripheral tolerance at homeostasis, and there is a growing appreciation for their role in modulating infectious disease immunity. Following acute and chronic infections, Tregs can restrict pathogen-specific T cell responses to limit immunopathology. However, it is unclear if Tregs mediate control of pathology and immunity in distal tissue sites during localized infections. We investigated the role of Tregs in immunity and disease in various tissue compartments in the context of “mild” vaginal Zika virus infection. We found that Tregs are critical to generating robust virus-specific CD8 T cell responses in the initial infection site. Further, Tregs limit inflammatory cytokines and immunopathology during localized infection; a dysregulated immune response in Treg-depleted mice leads to increased T cell infiltrates and immunopathology in both the vagina and the central nervous system (CNS). Importantly, these CNS infiltrates are not present at the same magnitude during infection of Treg-sufficient mice, in which there is no CNS immunopathology. Our data suggest that Tregs are necessary to generate a robust virus-specific response at the mucosal site of infection, while Treg-mediated restriction of bystander inflammation limits immunopathology both at the site of infection as well as distal tissue sites.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 923-938"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.06.010
Streptococcus pneumoniae colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting young children and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal-controlled human infection by analyzing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with data from a concurrent study in younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. However, older adults who were protected from colonization showed increased degranulation of cluster of differentiation 8+ T cells, both before and after pneumococcal challenge. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization.
肺炎链球菌在上呼吸道的定植与肺炎球菌疾病的发生有关，主要影响幼儿和老年人。随着全球人口的老龄化和并发症的增加，人们对这种感染的关注度也越来越高。我们通过分析鼻粘膜的细胞组成和基因表达，研究了老年人对肺炎球菌控制的人类感染的免疫反应。我们与同时在年轻人中进行的一项研究的数据进行了比较分析，结果发现，易受定植感染的老年人有不同的基因表达模式，其中突出的是中性粒细胞活化以及 CXCL9 和 CXCL10 水平的升高。与受到肺炎球菌挑战的年轻人不同，老年人在鼻腔定植肺炎球菌后并没有表现出单核细胞被招募到鼻粘膜中。然而，受到定植保护的老年人在肺炎球菌挑战前后都表现出 CD8+ T 细胞脱颗粒增加。这些研究结果表明，与年龄相关的细胞变化，尤其是粘膜炎症的增强，可能会使老年人更容易感染肺炎球菌。
{"title":"Inflammation of the nasal mucosa is associated with susceptibility to experimental pneumococcal challenge in older adults","authors":"","doi":"10.1016/j.mucimm.2024.06.010","DOIUrl":"10.1016/j.mucimm.2024.06.010","url":null,"abstract":"<div><div><em>Streptococcus pneumoniae</em> colonization in the upper respiratory tract is linked to pneumococcal disease development, predominantly affecting young children and older adults. As the global population ages and comorbidities increase, there is a heightened concern about this infection. We investigated the immunological responses of older adults to pneumococcal-controlled human infection by analyzing the cellular composition and gene expression in the nasal mucosa. Our comparative analysis with data from a concurrent study in younger adults revealed distinct gene expression patterns in older individuals susceptible to colonization, highlighted by neutrophil activation and elevated levels of CXCL9 and CXCL10. Unlike younger adults challenged with pneumococcus, older adults did not show recruitment of monocytes into the nasal mucosa following nasal colonization. However, older adults who were protected from colonization showed increased degranulation of cluster of differentiation 8+ T cells, both before and after pneumococcal challenge. These findings suggest age-associated cellular changes, in particular enhanced mucosal inflammation, that may predispose older adults to pneumococcal colonization.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 973-989"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.07.003
Gila Idelman , Christian F. Rizza , Sahiti Marella , Ankit Sharma , Somdutta Chakraborty , Hock L. Tay , Sunil Tomar , Varsha Ganesan , Charles F. Schuler IV , James R. Baker , Simon P. Hogan
<div><div>Mast cells (MCs) are derived from CD34<sup>+</sup> hematopoietic progenitors, consist of different subtypes, and are involved in several inflammatory conditions. However, our understanding of human MC developmental trajectories and subtypes has been limited by a scarcity of suitable cellular model systems. Herein, we developed an <em>in vitro</em> model of human MC differentiation from induced pluripotent stem cells (iPSC) to study human MC differentiation trajectories. Flow cytometry characterization of hemopoietic cells derived from the myeloid cells-forming complex (MCFC) revealed an initial increase in Lin<sup>-</sup> CD34<sup>+</sup> hematopoietic progenitors within Weeks 1–3, followed by an increase in CD34<sup>-</sup> CD45RA<sup>-</sup> SSC<sup>l</sup><sup>ow</sup> and SSC<sup>high</sup> hematopoietic cells. The Lin<sup>-</sup> CD34<sup>+</sup> hematopoietic progenitors consisted of SSC<sup>low</sup> CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>+</sup> FcεRI<sup>+</sup> populations that were β7-integrin<sup>high</sup> CD203c<sup>+</sup> and β7-integrin<sup>high</sup> CD203c<sup>-</sup> cells consistent with CMP<sup>Fc</sup><sup>ε</sup><sup>RI+</sup> cells. Flow cytometry and cytologic analyses of the CD34<sup>-</sup> Lin<sup>-</sup> (SSC<sup>low</sup>) population revealed hypogranular cell populations, predominantly characterized by CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>+</sup> FcεRI<sup>-</sup> β7-integrin<sup>low</sup> and CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>-</sup> FcεRI<sup>+</sup> β7-integrin<sup>Mid</sup> cells. Analyses of hypergranular SSC<sup>high</sup> cells identified Lin<sup>-</sup> CD34<sup>-</sup> CD45RA<sup>-</sup> c-Kit<sup>+</sup> FcεRI<sup>-</sup> and Lin<sup>-</sup> CD34<sup>-</sup> CD45RA<sup>-</sup> c-Kit<sup>+</sup> FcεRI<sup>+</sup> cells. scRNA-seq analysis of the cells harvested at week 4 of the MCFC culture revealed the presence of monocyte and granulocyte progenitors (n = 547 cells, 26.7 %), Erythrocyte / unknown (n = 85, 4.1 %), neutrophils / myelocytes (n = 211 cells, 10.2 %), mast cell progenitor 1 (n = 599, 29.1 %), mast cell progenitor 2 (n = 152, 7.4 %), committed mast cell precursor (n = 113, 5.5 %), and MCs (n = 353, 17.1 %). In silico analyses of the MC precursor and mature MC populations revealed transcriptionally distinct MC precursor subtype and mature MC states (CMA1<sup>+</sup> and CMA1<sup>-</sup> subtypes). Culturing MC precursor populations in MC maturation media (mast cell media II) led to homogenous mature MC populations as evidenced by high expression of high-affinity IgE receptor, metachromatic granules, presence of MC granule proteins (Tryptase and Chymase) and activation following substance P stimulation and FcεRI crosslinking. This human iPSC-based approach generates MC precursors and phenotypically mature and functional MC populations. This system will be a useful model to generate human MC populations and broaden our understanding of MC biology and transcr
肥大细胞（MC）来源于 CD34+ 造血祖细胞，由不同的亚型组成，参与多种炎症的治疗。然而，由于缺乏合适的细胞模型系统，我们对人类 MC 发育轨迹和亚型的了解受到了限制。在此，我们利用诱导多能干细胞（iPSC）建立了人类 MC 分化的体外模型，以研究人类 MC 的分化轨迹。流式细胞术鉴定了来自髓系细胞形成复合体（MCFC）的造血细胞，发现在第1-3周，Lin- CD34+造血祖细胞开始增加，随后CD34- CD45RA- SSCLow和SSChigh造血细胞增加。Lin- CD34+ 造血祖细胞由 SSClow CD45RA- CD123± c-Kit+ FcERI+ 群体组成，该群体为 β7-integrinhigh CD203c+ 和 β7-integrinhigh CD203c- 细胞，与 CMPFceRI+ 细胞一致。对CD34- Lin-（SSClow）群体的流式细胞术和细胞学分析显示了低颗粒细胞群，主要特征是CD45RA- CD123± c-Kit+ FcERI- β7-integrin-low和CD45RA- CD123± c-Kit- FcERI+ β7-integrin-Mid细胞。对超粒 SSChigh 细胞的分析发现了 Lin- CD34- CD45RA- c-Kit+ FceRI- 和 Lin- CD34- CD45RA- c-Kit+ FceRI+ 细胞。对 MCFC 培养第 4 周收获的细胞进行的 scRNA seq 分析显示存在单核细胞和粒细胞祖细胞（n = 547 个细胞，26.7 %）、红细胞/未知细胞（n = 85，4.1 %）、中性粒细胞/骨髓细胞（n = 211，10.2 %）、肥大细胞祖细胞 1（n = 599，29.1 %）、肥大细胞祖细胞 2（n = 152，7.4 %）、肥大细胞前体（n = 113，5.5 %）和肥大细胞（n = 353，17.1 %）。对肥大细胞前体和成熟肥大细胞群进行的硅学分析表明，肥大细胞前体亚型和成熟肥大细胞状态（CMA1+ 和 CMA1-亚型）在转录上截然不同。在 MC 成熟培养基（肥大细胞培养基 II）中培养 MC 前体群体可产生同质的成熟 MC 群体，表现为高亲和力 IgE 受体的高表达、变色颗粒、MC 颗粒蛋白（胰蛋白酶和糜蛋白酶）的存在以及物质 P 刺激和 FceRI 交联后的活化。这种基于人类 iPSC 的方法可产生 MC 前体和表型成熟的功能性 MC 群体。该系统将成为产生人类 MC 群体的有用模型，并拓宽我们对 MC 生物学和 MC 分化轨迹转录调控的理解。
{"title":"Inducible pluripotent stem cells to study human mast cell trajectories","authors":"Gila Idelman , Christian F. Rizza , Sahiti Marella , Ankit Sharma , Somdutta Chakraborty , Hock L. Tay , Sunil Tomar , Varsha Ganesan , Charles F. Schuler IV , James R. Baker , Simon P. Hogan","doi":"10.1016/j.mucimm.2024.07.003","DOIUrl":"10.1016/j.mucimm.2024.07.003","url":null,"abstract":"<div><div>Mast cells (MCs) are derived from CD34<sup>+</sup> hematopoietic progenitors, consist of different subtypes, and are involved in several inflammatory conditions. However, our understanding of human MC developmental trajectories and subtypes has been limited by a scarcity of suitable cellular model systems. Herein, we developed an <em>in vitro</em> model of human MC differentiation from induced pluripotent stem cells (iPSC) to study human MC differentiation trajectories. Flow cytometry characterization of hemopoietic cells derived from the myeloid cells-forming complex (MCFC) revealed an initial increase in Lin<sup>-</sup> CD34<sup>+</sup> hematopoietic progenitors within Weeks 1–3, followed by an increase in CD34<sup>-</sup> CD45RA<sup>-</sup> SSC<sup>l</sup><sup>ow</sup> and SSC<sup>high</sup> hematopoietic cells. The Lin<sup>-</sup> CD34<sup>+</sup> hematopoietic progenitors consisted of SSC<sup>low</sup> CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>+</sup> FcεRI<sup>+</sup> populations that were β7-integrin<sup>high</sup> CD203c<sup>+</sup> and β7-integrin<sup>high</sup> CD203c<sup>-</sup> cells consistent with CMP<sup>Fc</sup><sup>ε</sup><sup>RI+</sup> cells. Flow cytometry and cytologic analyses of the CD34<sup>-</sup> Lin<sup>-</sup> (SSC<sup>low</sup>) population revealed hypogranular cell populations, predominantly characterized by CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>+</sup> FcεRI<sup>-</sup> β7-integrin<sup>low</sup> and CD45RA<sup>-</sup> CD123<sup>±</sup> c-Kit<sup>-</sup> FcεRI<sup>+</sup> β7-integrin<sup>Mid</sup> cells. Analyses of hypergranular SSC<sup>high</sup> cells identified Lin<sup>-</sup> CD34<sup>-</sup> CD45RA<sup>-</sup> c-Kit<sup>+</sup> FcεRI<sup>-</sup> and Lin<sup>-</sup> CD34<sup>-</sup> CD45RA<sup>-</sup> c-Kit<sup>+</sup> FcεRI<sup>+</sup> cells. scRNA-seq analysis of the cells harvested at week 4 of the MCFC culture revealed the presence of monocyte and granulocyte progenitors (n = 547 cells, 26.7 %), Erythrocyte / unknown (n = 85, 4.1 %), neutrophils / myelocytes (n = 211 cells, 10.2 %), mast cell progenitor 1 (n = 599, 29.1 %), mast cell progenitor 2 (n = 152, 7.4 %), committed mast cell precursor (n = 113, 5.5 %), and MCs (n = 353, 17.1 %). In silico analyses of the MC precursor and mature MC populations revealed transcriptionally distinct MC precursor subtype and mature MC states (CMA1<sup>+</sup> and CMA1<sup>-</sup> subtypes). Culturing MC precursor populations in MC maturation media (mast cell media II) led to homogenous mature MC populations as evidenced by high expression of high-affinity IgE receptor, metachromatic granules, presence of MC granule proteins (Tryptase and Chymase) and activation following substance P stimulation and FcεRI crosslinking. This human iPSC-based approach generates MC precursors and phenotypically mature and functional MC populations. This system will be a useful model to generate human MC populations and broaden our understanding of MC biology and transcr","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1029-1044"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.07.005
Bingtai Lu , Yanfang Zhang , Jun Wang , Diyuan Yang , Ming Liu , Liuheyi Ma , Weijing Yi , Yufeng Liang , Yingyi Xu , Huifeng Fan , Wei Liu , Jue Tang , Sengqiang Zeng , Li Cai , Li Zhang , Junli Nie , Fen Zhang , Xiaoqiong Gu , Jaime S. Rosa Duque , Gen Lu , Yuxia Zhang
Human adenovirus (HAdV) pneumonia poses a major health burden for young children, however, factors that contribute to disease severity remain elusive. We analyzed immune cells from bronchoalveolar lavage (BAL) of children with HAdV pneumonia and found that CD19+CD21low B cells were significantly enriched in the BAL and were associated with increased autoantibody concentrations and disease severity. Myeloid cells, PD-1+CD4+ T helper cells and CD21low B cells formed tertiary lymphoid structures within the respiratory tracts. Myeloid cells promoted autoantibody production by expressing high amounts of B cell activating factor (BAFF). In contrast, PD-1+CD4+ T helper cells induced production of IgG1 and IgG3 antibodies but suppressed autoreactive IgGs by initiating B cell receptor editing. In summary, this study reveals cellular components involved in protective versus autoreactive immune pathways in the respiratory tract, and these findings provide potential therapeutic targets for severe HAdV lower respiratory tract infections.
人类腺病毒（HAdV）肺炎对幼儿的健康造成了重大负担，然而，导致疾病严重程度的因素仍然难以捉摸。我们分析了患 HAdV 肺炎儿童支气管肺泡灌洗液（BAL）中的免疫细胞，发现 CD19+CD21 低 B 细胞在 BAL 中明显富集，并与自身抗体浓度增加和疾病严重程度相关。髓系细胞、PD-1+CD4+ T 辅助细胞和 CD21low B 细胞在呼吸道内形成三级淋巴结构。髓系细胞通过表达大量的B细胞活化因子（BAFF）来促进自身抗体的产生。相反，PD-1+CD4+ T 辅助细胞诱导产生 IgG1 和 IgG3 抗体，但通过启动 B 细胞受体编辑抑制了自身反应性 IgG。总之，这项研究揭示了呼吸道中参与保护性免疫途径和自反应性免疫途径的细胞成分，这些发现为严重的HAdV下呼吸道感染提供了潜在的治疗靶点。
{"title":"PD1+CD4+ T cells promote receptor editing and suppress autoreactivity of CD19+CD21low B cells within the lower respiratory airways in adenovirus pneumonia","authors":"Bingtai Lu , Yanfang Zhang , Jun Wang , Diyuan Yang , Ming Liu , Liuheyi Ma , Weijing Yi , Yufeng Liang , Yingyi Xu , Huifeng Fan , Wei Liu , Jue Tang , Sengqiang Zeng , Li Cai , Li Zhang , Junli Nie , Fen Zhang , Xiaoqiong Gu , Jaime S. Rosa Duque , Gen Lu , Yuxia Zhang","doi":"10.1016/j.mucimm.2024.07.005","DOIUrl":"10.1016/j.mucimm.2024.07.005","url":null,"abstract":"<div><div>Human adenovirus (HAdV) pneumonia poses a major health burden for young children, however, factors that contribute to disease severity remain elusive. We analyzed immune cells from bronchoalveolar lavage (BAL) of children with HAdV pneumonia and found that CD19<sup>+</sup>CD21<sup>low</sup> B cells were significantly enriched in the BAL and were associated with increased autoantibody concentrations and disease severity. Myeloid cells, PD-1<sup>+</sup>CD4<sup>+</sup> T helper cells and CD21<sup>low</sup> B cells formed tertiary lymphoid structures within the respiratory tracts. Myeloid cells promoted autoantibody production by expressing high amounts of B cell activating factor (BAFF). In contrast, PD-1<sup>+</sup>CD4<sup>+</sup> T helper cells induced production of IgG1 and IgG3 antibodies but suppressed autoreactive IgGs by initiating B cell receptor editing. In summary, this study reveals cellular components involved in protective versus autoreactive immune pathways in the respiratory tract, and these findings provide potential therapeutic targets for severe HAdV lower respiratory tract infections.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1045-1059"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1016/j.mucimm.2024.03.008
Antibodies to SARS-CoV-2 on the mucosal surfaces of the respiratory tract are understood to contribute to protection against SARS-CoV-2 infection. We aimed to describe the prevalence, levels, and functionality of mucosal antibodies in the general Dutch population. Nasal samples were collected from 778 randomly selected participants, 1–90 years of age, nested within the nationwide prospective SARS-CoV-2 PIENTER corona serosurvey in the Netherlands. Spike-specific immunoglobulin (Ig)G was detected in the nasal samples of 94.6% (in case of the wild-type S1 variant) and 94.9% (Omicron BA.1) of the individuals, whereas 44.2% and 62.7% of the individuals were positive for wild-type and Omicron BA.1 S1 IgA, respectively. The lowest prevalence of mucosal antibodies was observed in children under 12 years of age. The prevalence and levels of IgA and IgG were higher in individuals with a history of SARS-CoV-2 infection. Mucosal antibodies inhibited the binding of Wuhan, Delta, and Omicron BA.1 receptor binding domain to human angiotensin-converting enzyme 2 in 94.4%, 95.4%, and 92.6% of the participants, respectively. Higher levels of mucosal antibodies were associated with a lower risk of future infection.
{"title":"Protective mucosal SARS-CoV-2 antibodies in the majority of the general population in the Netherlands","authors":"","doi":"10.1016/j.mucimm.2024.03.008","DOIUrl":"10.1016/j.mucimm.2024.03.008","url":null,"abstract":"<div><p>Antibodies to SARS-CoV-2 on the mucosal surfaces of the respiratory tract are understood to contribute to protection against SARS-CoV-2 infection. We aimed to describe the prevalence, levels, and functionality of mucosal antibodies in the general Dutch population. Nasal samples were collected from 778 randomly selected participants, 1–90 years of age, nested within the nationwide prospective SARS-CoV-2 PIENTER corona serosurvey in the Netherlands. Spike-specific immunoglobulin (Ig)G was detected in the nasal samples of 94.6% (in case of the wild-type S1 variant) and 94.9% (Omicron BA.1) of the individuals, whereas 44.2% and 62.7% of the individuals were positive for wild-type and Omicron BA.1 S1 IgA, respectively. The lowest prevalence of mucosal antibodies was observed in children under 12 years of age. The prevalence and levels of IgA and IgG were higher in individuals with a history of SARS-CoV-2 infection. Mucosal antibodies inhibited the binding of Wuhan, Delta, and Omicron BA.1 receptor binding domain to human angiotensin-converting enzyme 2 in 94.4%, 95.4%, and 92.6% of the participants, respectively. Higher levels of mucosal antibodies were associated with a lower risk of future infection.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 4","pages":"Pages 554-564"},"PeriodicalIF":7.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000278/pdfft?md5=cb5bf9cbb9f6c1513ad3a8f7ef4bfd9f&pid=1-s2.0-S1933021924000278-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1016/j.mucimm.2024.04.003
Immunoglobulin A (IgA) is the predominant mucosal antibody class with both anti- and pro-inflammatory roles1, 2, 3. However, the specific role of the IgA receptor cluster of differentiation (CD)89, expressed by a subset of natural killer (NK) cells, is poorly explored. We found that CD89 protein expression on circulating NK cells is infrequent in humans and rhesus macaques, but transcriptomic analysis showed ubiquitous CD89 expression, suggesting an inducible phenotype. Interestingly, CD89+ NK cells were more frequent in cord blood and mucosae, indicating a putative IgA-mediated NK cell function in the mucosae and infant immune system. CD89+ NK cells signaled through upregulated CD3 zeta chain (CD3ζ), spleen tyrosine kinase (Syk), zeta chain-associated protein kinase 70 (ZAP70), and signaling lymphocytic activation molecule family 1 (SLAMF1), but also showed high expression of inhibitory receptors such as killer cell lectin-like receptor subfamily G (KLRG1) and reduced activating NKp46 and NKp30. CD89-based activation or antibody-mediated cellular cytotoxicity with monomeric IgA1 reduced NK cell functions, while antibody-mediated cellular cytotoxicity with combinations of IgG and IgA2 was enhanced compared to IgG alone. These data suggest that functional CD89+ NK cells survey mucosal sites, but CD89 likely serves as regulatory receptor which can be further modulated depending on IgA and IgG subclass. Although the full functional niche of CD89+ NK cells remains unexplored, these intriguing data suggest the CD89 axis could represent a novel immunotherapeutic target in the mucosae or early life.
免疫球蛋白 A（IgA）是主要的粘膜抗体类别，具有抗炎和促炎作用1、2、3。然而，对自然杀伤（NK）细胞亚群所表达的 IgA 受体分化簇（CD）89 的特殊作用却知之甚少。我们发现，在人类和猕猴中，循环中的 NK 细胞很少有 CD89 蛋白表达，但转录组分析显示 CD89 表达无处不在，这表明它们具有诱导表型。有趣的是，CD89+ NK细胞在脐带血和粘膜中更为常见，这表明在粘膜和婴儿免疫系统中存在由IgA介导的NK细胞功能。CD89+ NK细胞通过上调的CD3 zeta链（CD3ζ）、脾脏酪氨酸激酶（Syk）、zeta链相关蛋白激酶70（ZAP70）和信号淋巴细胞活化分子家族1（SLAMF1）发出信号，但也显示出抑制性受体（如杀伤细胞凝集素样受体亚家族G（KLRG1））的高表达以及活化性NKp46和NKp30的减少。与单体 IgA1 相比，基于 CD89 的活化或抗体介导的细胞毒性降低了 NK 细胞的功能，而 IgG 和 IgA2 组合的抗体介导的细胞毒性则增强了。这些数据表明，功能性 CD89+ NK 细胞能勘测粘膜部位，但 CD89 可能是一种调节受体，可根据 IgA 和 IgG 亚类的不同而进一步调节。尽管 CD89+ NK 细胞的全部功能位点仍有待探索，但这些有趣的数据表明，CD89 轴可能是粘膜或生命早期的新型免疫治疗靶点。
{"title":"FcαRI (CD89) is upregulated on subsets of mucosal and circulating NK cells and regulates IgA-class specific signaling and functions","authors":"","doi":"10.1016/j.mucimm.2024.04.003","DOIUrl":"10.1016/j.mucimm.2024.04.003","url":null,"abstract":"<div><p>Immunoglobulin A (IgA) is the predominant mucosal antibody class with both anti- and pro-inflammatory roles<span><span>1</span></span>, <span><span>2</span></span>, <span><span>3</span></span>. However, the specific role of the IgA receptor cluster of differentiation (CD)89, expressed by a subset of natural killer (NK) cells, is poorly explored. We found that CD89 protein expression on circulating NK cells is infrequent in humans and rhesus macaques, but transcriptomic analysis showed ubiquitous CD89 expression, suggesting an inducible phenotype. Interestingly, CD89<sup>+</sup> NK cells were more frequent in cord blood and mucosae, indicating a putative IgA-mediated NK cell function in the mucosae and infant immune system. CD89<sup>+</sup> NK cells signaled through upregulated CD3 zeta chain (CD3ζ), spleen tyrosine kinase (Syk), zeta chain-associated protein kinase 70 (ZAP70), and signaling lymphocytic activation molecule family 1 (SLAMF1), but also showed high expression of inhibitory receptors such as killer cell lectin-like receptor subfamily G (KLRG1) and reduced activating NKp46 and NKp30. CD89-based activation or antibody-mediated cellular cytotoxicity with monomeric IgA1 reduced NK cell functions, while antibody-mediated cellular cytotoxicity with combinations of IgG and IgA2 was enhanced compared to IgG alone. These data suggest that functional CD89<sup>+</sup> NK cells survey mucosal sites, but CD89 likely serves as regulatory receptor which can be further modulated depending on IgA and IgG subclass. Although the full functional niche of CD89<sup>+</sup> NK cells remains unexplored, these intriguing data suggest the CD89 axis could represent a novel immunotherapeutic target in the mucosae or early life.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 4","pages":"Pages 692-699"},"PeriodicalIF":7.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000400/pdfft?md5=9a26af4ee3c7eb7c3872443e32ea46e1&pid=1-s2.0-S1933021924000400-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140767876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1016/j.mucimm.2024.04.004
Resident memory T cells (TRMs) help control local immune homeostasis and contribute to tissue-protective immune responses. The local cues that guide their differentiation and localization are poorly defined. We demonstrate that mucosal vascular addressin cell adhesion molecule 1, a ligand for the gut-homing receptor α4β7 integrin, in the presence of retinoic acid and transforming growth factor-β (TGF-β) provides a co-stimulatory signal that induces blood cluster of differentiation (CD8+ T cells to adopt a TRM-like phenotype. These cells express CD103 (integrin αE) and CD69, the two major TRM cell-surface markers, along with CD101. They also express C-C motif chemokine receptors 5 (CCR5) , C-C motif chemokine receptors 9 (CCR9), and α4β7, three receptors associated with gut homing. A subset also expresses E-cadherin, a ligand for αEβ7. Fluorescent lifetime imaging indicated an αEβ7 and E-cadherin cis interaction on the plasma membrane. This report advances our understanding of the signals that drive the differentiation of CD8+ T cells into resident memory T cells and provides a means to expand these cells in vitro, thereby affording an avenue to generate more effective tissue-specific immunotherapies.
{"title":"MAdCAM-1 co-stimulation combined with retinoic acid and TGF-β induces blood CD8+ T cells to adopt a gut CD101+ TRM phenotype","authors":"","doi":"10.1016/j.mucimm.2024.04.004","DOIUrl":"10.1016/j.mucimm.2024.04.004","url":null,"abstract":"<div><p>Resident memory T cells (T<sub>RM</sub>s) help control local immune homeostasis and contribute to tissue-protective immune responses. The local cues that guide their differentiation and localization are poorly defined. We demonstrate that mucosal vascular addressin cell adhesion molecule 1, a ligand for the gut-homing receptor α<sub>4</sub>β<sub>7</sub> integrin, in the presence of retinoic acid and transforming growth factor-β (TGF-β) provides a co-stimulatory signal that induces blood cluster of differentiation (CD8<sup>+</sup> T cells to adopt a T<sub>RM</sub>-like phenotype. These cells express CD103 (integrin α<sub>E</sub>) and CD69, the two major T<sub>RM</sub> cell-surface markers, along with CD101. They also express C-C motif chemokine receptors 5 (CCR5) , C-C motif chemokine receptors 9 (CCR9), and α<sub>4</sub>β<sub>7</sub>, three receptors associated with gut homing. A subset also expresses E-cadherin, a ligand for α<sub>E</sub>β<sub>7</sub>. Fluorescent lifetime imaging indicated an α<sub>E</sub>β<sub>7</sub> and E-cadherin cis interaction on the plasma membrane. This report advances our understanding of the signals that drive the differentiation of CD8<sup>+</sup> T cells into resident memory T cells and provides a means to expand these cells <em>in vitro</em>, thereby affording an avenue to generate more effective tissue-specific immunotherapies.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 4","pages":"Pages 700-712"},"PeriodicalIF":7.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000412/pdfft?md5=1de529852561125ba412d56f2a7634d4&pid=1-s2.0-S1933021924000412-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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