Pub Date : 2024-11-24DOI: 10.1016/j.mucimm.2024.11.008
Maud Heredia, Daniëlle M H Barendregt, Irma Tindemans, Renz C W Klomberg, Martine A Aardoom, Beatriz Calado, Léa M M Costes, Maria E Joosse, Daniëlle H Hulleman-van Haaften, Bastiaan Tuk, Lisette A van Berkel, Polychronis Kemos, Frank M Ruemmele, Nicholas M Croft, Johanna C Escher, Lissy de Ridder, Janneke N Samsom
CD4+ memory T cell (TM) reactivation drives chronicity in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis. Defects driving loss of TM regulation likely differ between patients but remain undefined. In health, approximately 40 % of circulating gut-homing CD38+TM express co-inhibitory receptor T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). TIGIT+CD38+TM have regulatory function while TIGITnegCD38+TM are enriched in IFN-γ-producing cells. We hypothesized TIGITnegCD38+TM are inflammatory and drive disease in a subgroup of IBD patients. We characterized TIGIT+CD38+TM in a uniquely large cohort of pediatric IBD patients from time of diagnosis into adulthood. Circulating TIGITnegCD38+TM frequencies were higher in a subgroup of therapy-naïve CD patients with high plasma IFN-γ and a more severe disease course. TIGITnegCD38+TM were highly enriched in HLA-DR+ and ex-Th17/Th1-like cells, high producers of IFN-γ. Cultures of healthy-adult-stimulated TM identified IL-12 as the only IBD-related inflammatory cytokine to drive the pathogenic ex-Th17-TIGITnegCD38+ phenotype. Moreover, IL12RB2 mRNA expression was higher in TIGITnegCD38+TM than TIGIT+CD38+TM, elevated in CD biopsies compared to controls, and correlated with severity of intestinal inflammation. Overall, we argue that in a subgroup of pediatric CD, increased IL-12 signaling drives reprogramming of Th17 to inflammatory Th1-like TIGITnegCD38+TM and causes more severe disease.
{"title":"Gut-homing and intestinal TIGIT<sup>neg</sup>CD38<sup>+</sup> memory T cells acquire an IL-12-induced, ex-Th17 pathogenic phenotype in a subgroup of Crohn's disease patients with a severe disease course.","authors":"Maud Heredia, Daniëlle M H Barendregt, Irma Tindemans, Renz C W Klomberg, Martine A Aardoom, Beatriz Calado, Léa M M Costes, Maria E Joosse, Daniëlle H Hulleman-van Haaften, Bastiaan Tuk, Lisette A van Berkel, Polychronis Kemos, Frank M Ruemmele, Nicholas M Croft, Johanna C Escher, Lissy de Ridder, Janneke N Samsom","doi":"10.1016/j.mucimm.2024.11.008","DOIUrl":"10.1016/j.mucimm.2024.11.008","url":null,"abstract":"<p><p>CD4<sup>+</sup> memory T cell (T<sub>M</sub>) reactivation drives chronicity in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis. Defects driving loss of T<sub>M</sub> regulation likely differ between patients but remain undefined. In health, approximately 40 % of circulating gut-homing CD38<sup>+</sup>T<sub>M</sub> express co-inhibitory receptor T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). TIGIT<sup>+</sup>CD38<sup>+</sup>T<sub>M</sub> have regulatory function while TIGIT<sup>neg</sup>CD38<sup>+</sup>T<sub>M</sub> are enriched in IFN-γ-producing cells. We hypothesized TIGIT<sup>neg</sup>CD38<sup>+</sup>T<sub>M</sub> are inflammatory and drive disease in a subgroup of IBD patients. We characterized TIGIT<sup>+</sup>CD38<sup>+</sup>T<sub>M</sub> in a uniquely large cohort of pediatric IBD patients from time of diagnosis into adulthood. Circulating TIGIT<sup>neg</sup>CD38<sup>+</sup>T<sub>M</sub> frequencies were higher in a subgroup of therapy-naïve CD patients with high plasma IFN-γ and a more severe disease course. TIGIT<sup>neg</sup>CD38<sup>+</sup>T<sub>M</sub> were highly enriched in HLA-DR<sup>+</sup> and ex-Th17/Th1-like cells, high producers of IFN-γ. Cultures of healthy-adult-stimulated T<sub>M</sub> identified IL-12 as the only IBD-related inflammatory cytokine to drive the pathogenic ex-Th17-TIGIT<sup>neg</sup>CD38<sup>+</sup> phenotype. Moreover, IL12RB2 mRNA expression was higher in TIGIT<sup>neg</sup>CD38<sup>+</sup>T<sub>M</sub> than TIGIT<sup>+</sup>CD38<sup>+</sup>T<sub>M</sub>, elevated in CD biopsies compared to controls, and correlated with severity of intestinal inflammation. Overall, we argue that in a subgroup of pediatric CD, increased IL-12 signaling drives reprogramming of Th17 to inflammatory Th1-like TIGIT<sup>neg</sup>CD38<sup>+</sup>T<sub>M</sub> and causes more severe disease.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.mucimm.2024.07.004
Joanne E. Konkel, Joshua R. Cox, Kelly Wemyss
Immune cells residing at the gingiva experience diverse and unique signals, tailoring their functions to enable them to appropriately respond to immunological challenges and maintain tissue integrity. The gingiva, defined as the mucosal barrier that surrounds and supports the teeth, is the only barrier site completely transected by a hard structure, the tooth. The tissue is damaged in early life during tooth eruption and chronically throughout life by the process of mastication. This occurs alongside challenges typical of barrier sites, including exposure to invading pathogens, the local commensal microbial community and environmental antigens. This review will focus on the immune network safeguarding gingival integrity, which is far less understood than that resident at other barrier sites. A detailed understanding of the gingiva-resident immune network is vital as it is the site of the inflammatory disease periodontitis, the most common chronic inflammatory condition in humans which has well-known detrimental systemic effects. Furthering our understanding of how the immune populations within the gingiva develop, are tailored in health, and how this is dysregulated in disease would further the development of effective therapies for periodontitis.
{"title":"Bite-sized immunology; damage and microbes educating immunity at the gingiva","authors":"Joanne E. Konkel, Joshua R. Cox, Kelly Wemyss","doi":"10.1016/j.mucimm.2024.07.004","DOIUrl":"10.1016/j.mucimm.2024.07.004","url":null,"abstract":"<div><div>Immune cells residing at the gingiva experience diverse and unique signals, tailoring their functions to enable them to appropriately respond to immunological challenges and maintain tissue integrity. The gingiva, defined as the mucosal barrier that surrounds and supports the teeth, is the only barrier site completely transected by a hard structure, the tooth. The tissue is damaged in early life during tooth eruption and chronically throughout life by the process of mastication. This occurs alongside challenges typical of barrier sites, including exposure to invading pathogens, the local commensal microbial community and environmental antigens. This review will focus on the immune network safeguarding gingival integrity, which is far less understood than that resident at other barrier sites. A detailed understanding of the gingiva-resident immune network is vital as it is the site of the inflammatory disease periodontitis, the most common chronic inflammatory condition in humans which has well-known detrimental systemic effects. Furthering our understanding of how the immune populations within the gingiva develop, are tailored in health, and how this is dysregulated in disease would further the development of effective therapies for periodontitis.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1141-1150"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748610","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.2024.07.007
Susan B. Morris , Ramon Ocadiz-Ruiz , Nobuhiro Asai , Carrie-Anne Malinczak , Andrew J Rasky , Grace K. Lombardo , Evan M. Velarde , Catherine Ptaschinski , Rachel L Zemans , Nicholas W. Lukacs , Wendy Fonseca
Early-life (EL) respiratory infections increase pulmonary disease risk, especially EL-Respiratory Syncytial Virus (EL-RSV) infections linked to asthma. Mechanisms underlying asthma predisposition remain unknown. In this study, we examined the long-term effects on the lung after four weeks post EL-RSV infection. We identified alterations in the lung epithelial cell, with a rise in the percentage of alveolar type 2 epithelial cells (AT2) and a decreased percentage of cells in the AT1 and AT2-AT1 subclusters, as well as upregulation of Bmp2 and Krt8 genes that are associated with AT2-AT1 trans-differentiation, suggesting potential defects in lung repair processes. We identified persistent upregulation of asthma-associated genes, including Il33. EL-RSV-infected mice allergen-challenged exhibited exacerbated allergic response, with significant upregulation of Il33 in the lung and AT2 cells. Similar long-term effects were observed in mice exposed to EL-IL-1β. Notably, treatment with IL-1ra during acute EL-RSV infection mitigated the long-term alveolar alterations and the allergen-exacerbated response. Finally, epigenetic modifications in the promoter of the Il33 gene were detected in AT2 cells harvested from EL-RSV and EL-IL1β groups, suggesting that long-term alteration in the epithelium after RSV infection is dependent on the IL-1β pathway. This study provides insight into the molecular mechanisms of asthma predisposition after RSV infection.
{"title":"Long-term alterations in lung epithelial cells after EL-RSV infection exacerbate allergic responses through IL-1β-induced pathways","authors":"Susan B. Morris , Ramon Ocadiz-Ruiz , Nobuhiro Asai , Carrie-Anne Malinczak , Andrew J Rasky , Grace K. Lombardo , Evan M. Velarde , Catherine Ptaschinski , Rachel L Zemans , Nicholas W. Lukacs , Wendy Fonseca","doi":"10.1016/j.mucimm.2024.07.007","DOIUrl":"10.1016/j.mucimm.2024.07.007","url":null,"abstract":"<div><div>Early-life (EL) respiratory infections increase pulmonary disease risk, especially EL-Respiratory Syncytial Virus (EL-RSV) infections linked to asthma. Mechanisms underlying asthma predisposition remain unknown. In this study, we examined the long-term effects on the lung after four weeks post EL-RSV infection. We identified alterations in the lung epithelial cell, with a rise in the percentage of alveolar type 2 epithelial cells (AT2) and a decreased percentage of cells in the AT1 and AT2-AT1 subclusters, as well as upregulation of <em>Bmp2</em> and <em>Krt8</em> genes that are associated with AT2-AT1 <em>trans</em>-differentiation, suggesting potential defects in lung repair processes. We identified persistent upregulation of asthma-associated genes, including <em>Il33</em>. EL-RSV-infected mice allergen-challenged exhibited exacerbated allergic response, with significant upregulation of <em>Il33</em> in the lung and AT2 cells. Similar long-term effects were observed in mice exposed to EL-IL-1β. Notably, treatment with IL-1ra during acute EL-RSV infection mitigated the long-term alveolar alterations and the allergen-exacerbated response. Finally, epigenetic modifications in the promoter of the <em>Il33</em> gene were detected in AT2 cells harvested from EL-RSV and EL-IL1β groups, suggesting that long-term alteration in the epithelium after RSV infection is dependent on the IL-1β pathway. This study provides insight into the molecular mechanisms of asthma predisposition after RSV infection.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1072-1088"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788701","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.2024.05.005
Upon infection, CD8+ T cells that have been primed in the draining lymph nodes migrate to the invaded tissue, where they receive cues prompting their differentiation into tissue-resident memory cells (Trm), which display niche-specific transcriptional features. Despite the importance of these cells, our understanding of their molecular landscape and the signals that dictate their development remains limited, particularly in specific anatomical niches such as the large intestine (LI). Here, we report that LI Trm-generated following oral infection exhibits a distinct transcriptional profile compared to Trm in other tissues. Notably, we observe that local cues play a crucial role in the preferential establishment of LI Trm, favoring precursors that migrate to the tissue early during infection. Our investigations identify cognate antigen recognition as a major driver of Trm differentiation at this anatomical site. Local antigen presentation not only promotes the proliferation of effector cells and memory precursors but also facilitates the acquisition of transcriptional features characteristic of gut Trm. Thus, antigen recognition in the LI favors the establishment of Trm by impacting T cell expansion and gene expression.
感染后，在引流淋巴结中被激活的 CD8+ T 细胞会迁移到受侵袭的组织，在那里它们会接收到促使它们分化为组织驻留记忆细胞（Trm）的信号，这些细胞会显示出龛位特异性转录特征。尽管这些细胞非常重要，但我们对其分子图谱和决定其发育的信号的了解仍然有限，尤其是在大肠（LI）等特定解剖龛位中。在这里，我们报告了口腔感染后产生的大肠Trm与其他组织中的Trm相比表现出不同的转录特征。值得注意的是，我们观察到局部线索在 LI Trm 的优先建立中起着至关重要的作用，有利于感染期间早期迁移到该组织的前体。我们的研究发现，同源抗原识别是这一解剖部位Trm分化的主要驱动力。局部抗原呈递不仅能促进效应细胞和记忆前体的增殖，还能促进获得肠道Trm特有的转录特征。因此，LI 中的抗原识别会影响 T 细胞的扩增和基因表达，从而有利于 Trm 的建立。
{"title":"Local antigen encounter promotes generation of tissue-resident memory T cells in the large intestine","authors":"","doi":"10.1016/j.mucimm.2024.05.005","DOIUrl":"10.1016/j.mucimm.2024.05.005","url":null,"abstract":"<div><div>Upon infection, CD8<sup>+</sup> T cells that have been primed in the draining lymph nodes migrate to the invaded tissue, where they receive cues prompting their differentiation into tissue-resident memory cells (Trm), which display niche-specific transcriptional features. Despite the importance of these cells, our understanding of their molecular landscape and the signals that dictate their development remains limited, particularly in specific anatomical niches such as the large intestine (LI). Here, we report that LI Trm-generated following oral infection exhibits a distinct transcriptional profile compared to Trm in other tissues. Notably, we observe that local cues play a crucial role in the preferential establishment of LI Trm, favoring precursors that migrate to the tissue early during infection. Our investigations identify cognate antigen recognition as a major driver of Trm differentiation at this anatomical site. Local antigen presentation not only promotes the proliferation of effector cells and memory precursors but also facilitates the acquisition of transcriptional features characteristic of gut Trm. Thus, antigen recognition in the LI favors the establishment of Trm by impacting T cell expansion and gene expression.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 810-824"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088085","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.2024.06.003
Exaggeration of type 2 immune responses promotes lung inflammation and altered lung development; however, eosinophils, despite expansion in the postnatal lung, have not been specifically assessed in the context of neonatal lung disease. Furthermore, early life factors including prematurity and respiratory infection predispose infants to chronic obstructive pulmonary disease later in life. To assess eosinophils in the developing lung and how they may contribute to chronic lung disease, we generated mice harboring eosinophil-specific deletion of the negative regulatory enzyme SH2 domain-containing inositol 5′ phosphatase-1. This increased the activity and number of pulmonary eosinophils in the developing lung, which was associated with impaired lung development, expansion of activated alveolar macrophages (AMφ), multinucleated giant cell formation, enlargement of airspaces, and fibrosis. Despite regression of eosinophils following completion of lung development, AMφ-dominated inflammation persisted, alongside lung damage. Bone marrow chimera studies showed that SH2 domain-containing inositol 5′ phosphatase-1-deficient eosinophils were not sufficient to drive inflammatory lung disease in adult steady-state mice but once inflammation and damage were present, it could not be resolved. Depletion of eosinophils during alveolarization alleviated pulmonary inflammation and lung pathology, demonstrating an eosinophil-intrinsic effect. These results show that the presence of activated eosinophils during alveolarization aggravates AMφs and promotes sustained inflammation and long-lasting lung pathology.
{"title":"Activated eosinophils in early life impair lung development and promote long-term lung damage","authors":"","doi":"10.1016/j.mucimm.2024.06.003","DOIUrl":"10.1016/j.mucimm.2024.06.003","url":null,"abstract":"<div><div>Exaggeration of type 2 immune responses promotes lung inflammation and altered lung development; however, eosinophils, despite expansion in the postnatal lung, have not been specifically assessed in the context of neonatal lung disease. Furthermore, early life factors including prematurity and respiratory infection predispose infants to chronic obstructive pulmonary disease later in life. To assess eosinophils in the developing lung and how they may contribute to chronic lung disease, we generated mice harboring eosinophil-specific deletion of the negative regulatory enzyme SH2 domain-containing inositol 5′ phosphatase-1. This increased the activity and number of pulmonary eosinophils in the developing lung, which was associated with impaired lung development, expansion of activated alveolar macrophages (AMφ), multinucleated giant cell formation, enlargement of airspaces, and fibrosis. Despite regression of eosinophils following completion of lung development, AMφ-dominated inflammation persisted, alongside lung damage. Bone marrow chimera studies showed that SH2 domain-containing inositol 5′ phosphatase-1-deficient eosinophils were not sufficient to drive inflammatory lung disease in adult steady-state mice but once inflammation and damage were present, it could not be resolved. Depletion of eosinophils during alveolarization alleviated pulmonary inflammation and lung pathology, demonstrating an eosinophil-intrinsic effect. These results show that the presence of activated eosinophils during alveolarization aggravates AMφs and promotes sustained inflammation and long-lasting lung pathology.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 871-891"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432275","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.2024.06.006
Dietary proteins are taken up by intestinal dendritic cells (DCs), cleaved into peptides, loaded to major histocompatibility complexes, and presented to T cells to generate an immune response. Amino acid (AA)-diets do not have the same effects because AAs cannot bind to major histocompatibility complex to activate T cells. Here, we show that impairment in regulatory T cell generation and loss of tolerance in mice fed a diet lacking whole protein is associated with major transcriptional changes in intestinal DCs including downregulation of genes related to DC maturation, activation and decreased gene expression of immune checkpoint molecules. Moreover, the AA-diet had a profound effect on microbiome composition, including an increase in Akkermansia muciniphilia and Oscillibacter and a decrease in Lactococcus lactis and Bifidobacterium. Although microbiome transfer experiments showed that AA-driven microbiome modulates intestinal DC gene expression, most of the unique transcriptional change in DC was linked to the absence of whole protein in the diet. Our findings highlight the importance of dietary proteins for intestinal DC function and mucosal tolerance.
膳食蛋白质会被肠道树突状细胞（DC）吸收，裂解成肽，装载到主要组织相容性配体（MHC）上，并呈现给 T 细胞以产生免疫反应。氨基酸（AA）饮食没有同样的效果，因为AA不能与MHC结合以激活T细胞。在这里，我们发现，以缺乏全蛋白的饮食喂养的小鼠的 Treg 细胞生成障碍和耐受性丧失与肠道 DC 的主要转录变化有关，包括 DC 成熟、活化和迁移相关基因的下调以及免疫检查点分子基因表达的减少。此外，AA饮食对微生物组的组成也有深远影响，包括Akkermansia muciniphilia和Oscillibacter的增加以及乳酸乳球菌和双歧杆菌的减少。虽然微生物组转移实验表明 AA 驱动的微生物组会调节肠道直肠基因表达，但直肠中大多数独特的转录变化都与膳食中缺乏全蛋白质有关。我们的研究结果凸显了膳食蛋白质对肠道直流电功能和粘膜耐受性的重要性。
{"title":"Dietary protein modulates intestinal dendritic cells to establish mucosal homeostasis","authors":"","doi":"10.1016/j.mucimm.2024.06.006","DOIUrl":"10.1016/j.mucimm.2024.06.006","url":null,"abstract":"<div><div>Dietary proteins are taken up by intestinal dendritic cells (DCs), cleaved into peptides, loaded to major histocompatibility complexes, and presented to T cells to generate an immune response. Amino acid (AA)-diets do not have the same effects because AAs cannot bind to major histocompatibility complex to activate T cells. Here, we show that impairment in regulatory T cell generation and loss of tolerance in mice fed a diet lacking whole protein is associated with major transcriptional changes in intestinal DCs including downregulation of genes related to DC maturation, activation and decreased gene expression of immune checkpoint molecules. Moreover, the AA-diet had a profound effect on microbiome composition, including an increase in <em>Akkermansia muciniphilia</em> and <em>Oscillibacter</em> and a decrease in <em>Lactococcus lactis</em> and <em>Bifidobacterium</em>. Although microbiome transfer experiments showed that AA-driven microbiome modulates intestinal DC gene expression, most of the unique transcriptional change in DC was linked to the absence of whole protein in the diet. Our findings highlight the importance of dietary proteins for intestinal DC function and mucosal tolerance.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 911-922"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458190","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.2024.07.001
The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar “Western” diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.
{"title":"Western diet reduces small intestinal intraepithelial lymphocytes via FXR-Interferon pathway","authors":"","doi":"10.1016/j.mucimm.2024.07.001","DOIUrl":"10.1016/j.mucimm.2024.07.001","url":null,"abstract":"<div><div>The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar “Western” diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1019-1028"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590827","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.2024.07.002
Sumanta K. Naik, Michael E. McNehlan, Yassin Mreyoud, Rachel L. Kinsella, Asya Smirnov, Chanchal Sur Chowdhury, Samuel R. McKee, Neha Dubey, Reilly Woodson, Darren Kreamalmeyer, Christina L. Stallings
Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells. However, what IRGM1-mediated pathway is necessary to control Mtb infection in vivo and the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesis in vivo and found that Irgm1 deletion leads to higher levels of IRGM3-dependent type I interferon signaling. The increased type I interferon signaling precludes T cell expansion during Mtb infection. The absence of Mtb-specific T cell expansion in Irgm1−/− mice results in uncontrolled Mtb infection in neutrophils and alveolar macrophages, which directly contributes to susceptibility to infection. Together, our studies reveal that IRGM1 is required to promote T cell-mediated control of Mtb infection in neutrophils, which is essential for the survival of Mtb-infected mice. These studies also uncover new ways type I interferon signaling can impact TH1 immune responses.
IRGM基因的多态性与人类对结核病的易感性有关。Irgm的小鼠直向同源物Irgm1也是控制小鼠结核分枝杆菌（Mtb）感染的关键。与IRGM1活性相关的多个过程可能会影响宿主对Mtb感染的反应，包括在自噬介导的病原体清除和活化T细胞扩增中的作用。然而，IRGM1 介导的哪种途径是控制体内 Mtb 感染所必需的，以及这种控制的机理基础仍然未知。我们剖析了IRGM1对体内Mtb发病的免疫控制的贡献，发现Irgm1缺失会导致IRGM3依赖的I型干扰素信号水平升高。I型干扰素信号的增加阻止了T细胞在Mtb感染期间的扩增。Irgm1-/-小鼠缺乏Mtb特异性T细胞扩增，导致中性粒细胞和肺泡巨噬细胞中的Mtb感染失控，从而直接导致感染易感性。总之，我们的研究揭示了IRGM1是促进T细胞介导的中性粒细胞Mtb感染控制所必需的，这对Mtb感染小鼠的存活至关重要。这些研究还发现了 I 型干扰素信号转导影响 TH1 免疫反应的新途径。
{"title":"Type I IFN signaling in the absence of IRGM1 promotes M. tuberculosis replication in immune cells by suppressing T cell responses","authors":"Sumanta K. Naik, Michael E. McNehlan, Yassin Mreyoud, Rachel L. Kinsella, Asya Smirnov, Chanchal Sur Chowdhury, Samuel R. McKee, Neha Dubey, Reilly Woodson, Darren Kreamalmeyer, Christina L. Stallings","doi":"10.1016/j.mucimm.2024.07.002","DOIUrl":"10.1016/j.mucimm.2024.07.002","url":null,"abstract":"<div><div>Polymorphisms in the <em>IRGM</em> gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of <em>Irgm</em>, <em>Irgm1</em>, is also essential for controlling <em>Mycobacterium tuberculosis</em> (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells. However, what IRGM1-mediated pathway is necessary to control Mtb infection <em>in vivo</em> and the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesis <em>in vivo</em> and found that <em>Irgm1</em> deletion leads to higher levels of IRGM3-dependent type I interferon signaling. The increased type I interferon signaling precludes T cell expansion during Mtb infection. The absence of Mtb-specific T cell expansion in <em>Irgm1</em><sup>−/−</sup> mice results in uncontrolled Mtb infection in neutrophils and alveolar macrophages, which directly contributes to susceptibility to infection. Together, our studies reveal that IRGM1 is required to promote T cell-mediated control of Mtb infection in neutrophils, which is essential for the survival of Mtb-infected mice. These studies also uncover new ways type I interferon signaling can impact T<sub>H</sub>1 immune responses.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1114-1127"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748613","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.2024.07.008
Jacob K. Flynn , Alexandra M. Ortiz , Ivan Vujkovic-Cvijin , Hugh C. Welles , Jennifer Simpson , Fabiola M. Castello Casta , Debra S. Yee , Andrew R. Rahmberg , Kelsie L. Brooks , Marlon De Leon , Samantha Knodel , Kenzie Birse , Laura Noel-Romas , Anshu Deewan , Yasmine Belkaid , Adam Burgener , Jason M. Brenchley
Microbial translocation is a significant contributor to chronic inflammation in people living with HIV (PLWH) and is associated with increased mortality and morbidity in individuals treated for long periods with antiretrovirals. The use of therapeutics to treat microbial translocation has yielded mixed effects, in part, because the species and mechanisms contributing to translocation in HIV remain incompletely characterized. To characterize translocating bacteria, we cultured translocators from chronically SIV-infected rhesus macaques. Proteomic profiling of these bacteria identified cytosine-specific methyltransferases as a common feature and therefore, a potential driver of translocation. Treatment of translocating bacteria with the cytosine methyltransferase inhibitor decitabine significantly impaired growth for several species in vitro. In rhesus macaques, oral treatment with decitabine led to some transient decreases in translocator taxa in the gut microbiome. These data provide mechanistic insight into bacterial translocation in lentiviral infection and explore a novel therapeutic intervention that may improve the prognosis of PLWH.
{"title":"Translocating bacteria in SIV infection are not stochastic and preferentially express cytosine methyltransferases","authors":"Jacob K. Flynn , Alexandra M. Ortiz , Ivan Vujkovic-Cvijin , Hugh C. Welles , Jennifer Simpson , Fabiola M. Castello Casta , Debra S. Yee , Andrew R. Rahmberg , Kelsie L. Brooks , Marlon De Leon , Samantha Knodel , Kenzie Birse , Laura Noel-Romas , Anshu Deewan , Yasmine Belkaid , Adam Burgener , Jason M. Brenchley","doi":"10.1016/j.mucimm.2024.07.008","DOIUrl":"10.1016/j.mucimm.2024.07.008","url":null,"abstract":"<div><div>Microbial translocation is a significant contributor to chronic inflammation in people living with HIV (PLWH) and is associated with increased mortality and morbidity in individuals treated for long periods with antiretrovirals. The use of therapeutics to treat microbial translocation has yielded mixed effects, in part, because the species and mechanisms contributing to translocation in HIV remain incompletely characterized. To characterize translocating bacteria, we cultured translocators from chronically SIV-infected rhesus macaques. Proteomic profiling of these bacteria identified cytosine-specific methyltransferases as a common feature and therefore, a potential driver of translocation. Treatment of translocating bacteria with the cytosine methyltransferase inhibitor decitabine significantly impaired growth for several species in vitro. In rhesus macaques, oral treatment with decitabine led to some transient decreases in translocator taxa in the gut microbiome. These data provide mechanistic insight into bacterial translocation in lentiviral infection and explore a novel therapeutic intervention that may improve the prognosis of PLWH.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1089-1101"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875367","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.2024.06.012
A vaccine is needed to combat the Chlamydia epidemic. Replication-deficient viral vectors are safe and induce antigen-specific T-cell memory. We tested the ability of intramuscular immunization with modified vaccinia Ankara (MVA) virus or chimpanzee adenovirus (ChAd) expressing chlamydial outer membrane protein (OmcB) or the secreted protein, chlamydial protease-like activating factor (CPAF), to enhance T-cell immunity and protection in mice previously infected with plasmid-deficient Chlamydia muridarum CM972 and elicit protection in naïve mice. MVA.OmcB or MVA.CPAF increased antigen-specific T cells in CM972-immune mice ∼150 and 50-fold, respectively, but failed to improve bacterial clearance. ChAd.OmcB/MVA.OmcB prime-boost immunization of naïve mice elicited a cluster of differentiation (CD) 8-dominant T-cell response dominated by cluster of differentiation (CD)8 T cells that failed to protect. ChAd.CPAF/ChAd.CPAF prime-boost also induced a CD8-dominant response with a marginal reduction in burden. Challenge of ChAd.CPAF-immunized mice genetically deficient in CD4 or CD8 T cells showed that protection was entirely CD4-dependent. CD4-deficient mice had prolonged infection, whereas CD8-deficient mice had higher frequencies of CPAF-specific CD4 T cells, earlier clearance, and reduced burden than wild-type controls. These data reinforce the essential nature of the CD4 T-cell response in protection from chlamydial genital infection in mice and the need for vaccine platforms that drive CD4-dominant responses.
需要一种疫苗来防治衣原体流行病。复制缺陷病毒载体既安全又能诱导抗原特异性 T 细胞记忆。我们测试了用表达衣原体外膜蛋白OmcB或分泌蛋白CPAF的改良安卡拉疫苗病毒（MVA）或黑猩猩腺病毒（ChAd）进行肌肉注射免疫，增强小鼠T细胞免疫力和保护力的能力，这些小鼠以前感染过质粒缺陷的鼠衣原体CM972，并在天真小鼠中产生保护作用。MVA.OmcB 或 MVA.CPAF 可使 CM972-免疫小鼠的抗原特异性 T 细胞分别增加 150 倍和 50 倍，但未能提高细菌清除率。ChAd.OmcB/MVA.OmcB对幼稚小鼠的原代增强免疫引起了CD8占优势的T细胞反应，但未能起到保护作用。ChAd.CPAF/ChAd.CPAF原代增强免疫也能诱导CD8优势反应，但负担略有减少。对基因上缺乏 CD4 或 CD8 T 细胞的 ChAd.CPAF 免疫小鼠的挑战表明，保护作用完全依赖于 CD4。与野生型对照组相比，CD4缺陷小鼠的感染时间延长，而CD8缺陷小鼠的CPAF特异性CD4 T细胞频率更高，清除时间更早，负担更轻。这些数据进一步证实了 CD4 T 细胞应答在保护小鼠免受衣原体生殖器感染中的重要作用，同时也证明了开发 CD4 主导应答的疫苗平台的必要性。
{"title":"Viral-vectored boosting of OmcB- or CPAF-specific T-cell responses fail to enhance protection from Chlamydia muridarum in infection-immune mice and elicits a non-protective CD8-dominant response in naïve mice","authors":"","doi":"10.1016/j.mucimm.2024.06.012","DOIUrl":"10.1016/j.mucimm.2024.06.012","url":null,"abstract":"<div><div>A vaccine is needed to combat the <em>Chlamydia</em> epidemic. Replication-deficient viral vectors are safe and induce antigen-specific T-cell memory. We tested the ability of intramuscular immunization with modified vaccinia Ankara (MVA) virus or chimpanzee adenovirus (ChAd) expressing chlamydial outer membrane protein (OmcB) or the secreted protein, chlamydial protease-like activating factor (CPAF), to enhance T-cell immunity and protection in mice previously infected with plasmid-deficient <em>Chlamydia muridarum</em> CM972 and elicit protection in naïve mice. MVA.OmcB or MVA.CPAF increased antigen-specific T cells in CM972-immune mice ∼150 and 50-fold, respectively, but failed to improve bacterial clearance. ChAd.OmcB/MVA.OmcB prime-boost immunization of naïve mice elicited a cluster of differentiation (CD) 8-dominant T-cell response dominated by cluster of differentiation (CD)8 T cells that failed to protect. ChAd.CPAF/ChAd.CPAF prime-boost also induced a CD8-dominant response with a marginal reduction in burden. Challenge of ChAd.CPAF-immunized mice genetically deficient in CD4 or CD8 T cells showed that protection was entirely CD4-dependent. CD4-deficient mice had prolonged infection, whereas CD8-deficient mice had higher frequencies of CPAF-specific CD4 T cells, earlier clearance, and reduced burden than wild-type controls. These data reinforce the essential nature of the CD4 T-cell response in protection from chlamydial genital infection in mice and the need for vaccine platforms that drive CD4-dominant responses.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 5","pages":"Pages 1005-1018"},"PeriodicalIF":7.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538196","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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