Pub Date : 2025-10-01Epub Date: 2025-07-17DOI: 10.1016/j.mucimm.2025.07.005
Sara Alonso , Harsimran Kaur , Luo Jia , Mai-Uyen Nguyen , Alyssa Laguerta , Andrew Fong , Neema Skariah , Rafael J. Argüello , Michael P. Verzi , Mahima Swamy , Ken S. Lau , Karen L. Edelblum
Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative γδ IEL (γδHYP) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory γδ T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naïve-like CD39neg γδ IEL to a more mature, tissue-adapted CD39hi IEL population. We found that TCRγδ activation drives CD122-mediated CD39 upregulation on γδHYP IELs and increased mucosal IL-15 further amplifies CD39 expression in these cells. Further investigation revealed that CD39 induction requires sustained exposure to the γδHYP-associated microbiota. Moreover, CD39hi γδ IELs exhibit a reduced capacity to produce pro-inflammatory cytokine, which may explain the lack of histopathology in γδHYP mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on γδHYP IELs, leading to the expansion of γδ IELs with regulatory potential.
{"title":"Microbiota promote enhanced CD39 expression in γδ intraepithelial lymphocytes through the activation of TCR and IL-15 signaling","authors":"Sara Alonso , Harsimran Kaur , Luo Jia , Mai-Uyen Nguyen , Alyssa Laguerta , Andrew Fong , Neema Skariah , Rafael J. Argüello , Michael P. Verzi , Mahima Swamy , Ken S. Lau , Karen L. Edelblum","doi":"10.1016/j.mucimm.2025.07.005","DOIUrl":"10.1016/j.mucimm.2025.07.005","url":null,"abstract":"<div><div>Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative γδ IEL (γδ<sup>HYP</sup>) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory γδ T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naïve-like CD39<sup>neg</sup> γδ IEL to a more mature, tissue-adapted CD39<sup>hi</sup> IEL population. We found that TCRγδ activation drives CD122-mediated CD39 upregulation on γδ<sup>HYP</sup> IELs and increased mucosal IL-15 further amplifies CD39 expression in these cells. Further investigation revealed that CD39 induction requires sustained exposure to the γδ<sup>HYP</sup>-associated microbiota. Moreover, CD39<sup>hi</sup> γδ IELs exhibit a reduced capacity to produce pro-inflammatory cytokine, which may explain the lack of histopathology in γδ<sup>HYP</sup> mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on γδ<sup>HYP</sup> IELs, leading to the expansion of γδ IELs with regulatory potential.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1184-1198"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668044","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 : 2025-10-01Epub Date: 2025-06-07DOI: 10.1016/j.mucimm.2025.06.002
Alexandra M. Ortiz , Fabiola Castello Casta , Elizabeth G. Bodykevich , Jacob K. Flynn , Christine M. Fennessey , Kelsie Brooks , Delmy Ruiz , Debra S. Yee , Jennifer Simpson , Andrew R. Rahmberg , Brandon F. Keele , Jason M. Brenchley
Chronic gastrointestinal diseases are a significant global health burden that can require the use of gastrointestinal-cleansing regimens for diagnostics or therapeutic treatment. These regimens are beneficial for facilitating surgical preparation, drug delivery, colorectal cancer screenings, and personal use is common among proponents of natural health and among certain populations at high risk of HIV acquisition. It remains unclear, however, whether repeated clearance of the colonic microbiome induces persistent changes in the microbiome, intestinal immunity, and viral disease susceptibility. We addressed these parameters by repeatedly administering iso-osmolar enemas to rhesus macaques prior to low-dose intra-rectal challenge with simian immunodeficiency virus (SIV). Considering both longitudinal and cross-sectional analyses, we observed no consistent changes in the fecal microbiome or intestinal immune parameters of treated animals, nor were significant differences observed in susceptibility to SIV acquisition. Unexpectedly, enema-treated animals exhibited significantly lower setpoint viral loads after infection, although we were unable to clearly identify attributing causes. Our study demonstrates that repeated microbiome clearance using clinically administered iso-osmolar enemas is not sufficient to restructure the fecal microbiome, perturb intestinal immune parameters, or increase susceptibility to mucosal SIV challenge. This research framework serves as a model for the development of colonic-administered diagnostics and interventions.
{"title":"Repeated enema administration in rhesus macaques is not sufficient to promote bacterial dysbiosis or gastrointestinal dysfunction","authors":"Alexandra M. Ortiz , Fabiola Castello Casta , Elizabeth G. Bodykevich , Jacob K. Flynn , Christine M. Fennessey , Kelsie Brooks , Delmy Ruiz , Debra S. Yee , Jennifer Simpson , Andrew R. Rahmberg , Brandon F. Keele , Jason M. Brenchley","doi":"10.1016/j.mucimm.2025.06.002","DOIUrl":"10.1016/j.mucimm.2025.06.002","url":null,"abstract":"<div><div>Chronic gastrointestinal diseases are a significant global health burden that can require the use of gastrointestinal-cleansing regimens for diagnostics or therapeutic treatment. These regimens are beneficial for facilitating surgical preparation, drug delivery, colorectal cancer screenings, and personal use is common among proponents of natural health and among certain populations at high risk of HIV acquisition. It remains unclear, however, whether repeated clearance of the colonic microbiome induces persistent changes in the microbiome, intestinal immunity, and viral disease susceptibility. We addressed these parameters by repeatedly administering <em>iso</em>-osmolar enemas to rhesus macaques prior to low-dose intra-rectal challenge with simian immunodeficiency virus (SIV). Considering both longitudinal and cross-sectional analyses, we observed no consistent changes in the fecal microbiome or intestinal immune parameters of treated animals, nor were significant differences observed in susceptibility to SIV acquisition. Unexpectedly, enema-treated animals exhibited significantly lower setpoint viral loads after infection, although we were unable to clearly identify attributing causes. Our study demonstrates that repeated microbiome clearance using clinically administered <em>iso</em>-osmolar enemas is not sufficient to restructure the fecal microbiome, perturb intestinal immune parameters, or increase susceptibility to mucosal SIV challenge. This research framework serves as a model for the development of colonic-administered diagnostics and interventions.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1036-1046"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258606","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 : 2025-10-01Epub Date: 2025-07-19DOI: 10.1016/j.mucimm.2025.07.004
Ying Zhu , Jiayao Zhou , Ru Tang , Shiyao Zhang , Chunyu Luo , Yuelong Gu , Shilei Pu , Song Mao , Hai Lin , Haibo Ye , Zhipeng Li , Weitian Zhang
Apolipoprotein E (APOE) expressed by macrophages modulates allergic inflammation and remodeling of the lower airway. However, its expression and functions in chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear. We sought to investigate the involvement of macrophage derived APOE in the pathogenesis of CRSwNP. APOE expression was evaluated in single cell RNA sequencing data and then validated in tissues from healthy controls (HCs), chronic rhinosinusitis without nasal polyps (CRSsNP) and CRSwNP patients. We found that APOE expression was elevated in M2 macrophages of both eosinophilic and non-eosinophilic CRSwNP patients. APOE protein was increased in nasal secretions from CRSwNP patients compared to HCs and CRSsNP patients, while no significant differences were found in serum samples. TGF-β induced APOE secretion in both THP-1 and peripheral blood mononuclear cell (PBMC) differentiated macrophages in vitro. Fibroblast LRP1 was predicted as a potential receptor, with expression correlating positively with APOE levels. In primary nasal fibroblasts, APOE induced MMP2 and MMP9 expression through LRP1-dependent ERK activation. CRSwNP murine model was established in wild type and Apoe-/- mice, which indicated that Apoe deficiency attenuated NP-like lesions formation and the expression of Lrp1 and Mmp2 in nasal mucosa. Our data demonstrated that APOE expression is increased in macrophages from both eosinophilic and non-eosinophilic CRSwNP and promotes fibroblast MMP2 and MMP9 expression via LRP1-ERK signaling, which may contribute to tissue remodeling in CRSwNP.
{"title":"M2 macrophage-derived Apolipoprotein E promotes fibroblast MMPs expression via LRP1-ERK signaling in chronic rhinosinusitis with nasal polyps","authors":"Ying Zhu , Jiayao Zhou , Ru Tang , Shiyao Zhang , Chunyu Luo , Yuelong Gu , Shilei Pu , Song Mao , Hai Lin , Haibo Ye , Zhipeng Li , Weitian Zhang","doi":"10.1016/j.mucimm.2025.07.004","DOIUrl":"10.1016/j.mucimm.2025.07.004","url":null,"abstract":"<div><div>Apolipoprotein E (APOE) expressed by macrophages modulates allergic inflammation and remodeling of the lower airway. However, its expression and functions in chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear. We sought to investigate the involvement of macrophage derived APOE in the pathogenesis of CRSwNP. APOE expression was evaluated in single cell RNA sequencing data and then validated in tissues from healthy controls (HCs), chronic rhinosinusitis without nasal polyps (CRSsNP) and CRSwNP patients. We found that APOE expression was elevated in M2 macrophages of both eosinophilic and non-eosinophilic CRSwNP patients. APOE protein was increased in nasal secretions from CRSwNP patients compared to HCs and CRSsNP patients, while no significant differences were found in serum samples. TGF-β induced APOE secretion in both THP-1 and peripheral blood mononuclear cell (PBMC) differentiated macrophages <em>in vitro</em>. Fibroblast LRP1 was predicted as a potential receptor, with expression correlating positively with APOE levels. In primary nasal fibroblasts, APOE induced MMP2 and MMP9 expression through LRP1-dependent ERK activation. CRSwNP murine model was established in wild type and <em>Apoe</em><sup>-/-</sup> mice, which indicated that <em>Apoe</em> deficiency attenuated NP-like lesions formation and the expression of <em>Lrp1</em> and <em>Mmp2</em> in nasal mucosa. Our data demonstrated that APOE expression is increased in macrophages from both eosinophilic and non-eosinophilic CRSwNP and promotes fibroblast MMP2 and MMP9 expression via LRP1-ERK signaling, which may contribute to tissue remodeling in CRSwNP.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1171-1183"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682800","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}
Oral lichen planus (OLP) is a chronic inflammatory disorder with autoimmune features and malignant transformation risk, lacking a definitive treatment, with CD4+ T cells being pivotal in its pathogenesis. Dysbiosis, an imbalance in the microbiome, is linked to various autoimmune and inflammatory diseases, where CD4+ T cells play a significant role. Given these insights, the development of OLP might be influenced by dysbiosis. This study investigates the association between dysbiosis and CD4+ T cells in OLP. We collected stool and saliva samples from OLP patients, conducting 16S rRNA gene analysis and mass spectrometry, and assessed CD4+ T cell characteristics in lesions through multiplex immunofluorescence and single-cell RNA sequencing. Peripheral blood samples were subjected to flow cytometry and cell culture assays. Results showed extensive gut dysbiosis in OLP patients, notably a reduction in short-chain fatty acid (SCFA)-producing bacteria essential for regulatory T cell (Treg) differentiation. While various CD4+ T cell subsets, including Tregs, were present in tissues, these Tregs as unresponsive to specific antigens, showing reduced immunosuppressive molecule expression. The decline in SCFA-producing bacteria correlated with fewer activated Tregs in tissues and blood. These findings suggest that gut dysbiosis may contribute to OLP by impairing Treg regulation, influencing disease pathogenesis.
{"title":"Dysbiosis of the gut microbiome may contribute to the pathogenesis of oral lichen planus through Treg dysregulation","authors":"Shiho Yokomizo , Naoki Kaneko , Hu Chen , Lijing Yan , Shoji Tsuji , Shohei Akagawa , Junsei Sameshima , Tomoki Sueyoshi , Haruki Nagano , Yuka Miyahara , Yasuhisa Kamikaseda , Hajime Kido , Yoshikazu Hayashi , Masaki Yamauchi , Tamotsu Kiyoshima , Yuichi Goto , Yukiko Ohyama , Kazunari Kaneko , Masafumi Moriyama , Shintaro Kawano","doi":"10.1016/j.mucimm.2025.05.009","DOIUrl":"10.1016/j.mucimm.2025.05.009","url":null,"abstract":"<div><div>Oral lichen planus (OLP) is a chronic inflammatory disorder with autoimmune features and malignant transformation risk, lacking a definitive treatment, with CD4<sup>+</sup> T cells being pivotal in its pathogenesis. Dysbiosis, an imbalance in the microbiome, is linked to various autoimmune and inflammatory diseases, where CD4<sup>+</sup> T cells play a significant role. Given these insights, the development of OLP might be influenced by dysbiosis. This study investigates the association between dysbiosis and CD4<sup>+</sup> T cells in OLP. We collected stool and saliva samples from OLP patients, conducting 16S rRNA gene analysis and mass spectrometry, and assessed CD4<sup>+</sup> T cell characteristics in lesions through multiplex immunofluorescence and single-cell RNA sequencing. Peripheral blood samples were subjected to flow cytometry and cell culture assays. Results showed extensive gut dysbiosis in OLP patients, notably a reduction in short-chain fatty acid (SCFA)-producing bacteria essential for regulatory T cell (Treg) differentiation. While various CD4<sup>+</sup> T cell subsets, including Tregs, were present in tissues, these Tregs as unresponsive to specific antigens, showing reduced immunosuppressive molecule expression. The decline in SCFA-producing bacteria correlated with fewer activated Tregs in tissues and blood. These findings suggest that gut dysbiosis may contribute to OLP by impairing Treg regulation, influencing disease pathogenesis.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1013-1026"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275439","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 : 2025-10-01Epub Date: 2025-06-24DOI: 10.1016/j.mucimm.2025.06.007
Mohan Liu , Rodolfo D. Vicetti Miguel , Kristen Aceves , Thomas L. Cherpes
Desmosomes are junctional complexes that confer mechanical strength and enhance barrier protection at mucosal epithelial surfaces by anchoring intermediate filaments to plasma membrane. These roles are best defined in cutaneous epithelium, but we previously identified lower levels of the desmosomal cadherins desmoglein-1 (DSG1) and desmocollin-1 (DSC1) and loss of barrier function in vaginal epithelium of mice treated systemically with the progestin depot medroxyprogesterone acetate (DMPA). We also showed these changes were avoided in mice treated with both DMPA and a conjugated equine estrogen vaginal cream. We extend these earlier results in the current investigation, identifying ephrin-A3 (EFNA3) as an important regulator of desmosomal cadherin gene expression in murine vaginal epithelial tissue. Moreover, topical treatment of mice with recombinant EFNA3 (rEFNA3) significantly increased vaginal expression of DSG1 and partially reversed the loss of vaginal epithelial barrier function induced by DMPA treatment. Consistent with this improvement in vaginal epithelial barrier protection, mortality caused by genital herpes simplex virus type 2 infection was delayed, but not prevented, in mice administered DMPA and rEFNA3 vs. DMPA alone. Together, current studies identify EFNA3 as a key regulator of desmosomal structure and function in vaginal epithelium and newly suggest that ephrin-Eph signaling pathways will provide an important target for enhancing vaginal epithelial integrity and barrier function.
{"title":"Exogenous ephrin-A3 reverses loss of vaginal epithelial barrier protection in progestin-treated mice","authors":"Mohan Liu , Rodolfo D. Vicetti Miguel , Kristen Aceves , Thomas L. Cherpes","doi":"10.1016/j.mucimm.2025.06.007","DOIUrl":"10.1016/j.mucimm.2025.06.007","url":null,"abstract":"<div><div>Desmosomes are junctional complexes that confer mechanical strength and enhance barrier protection at mucosal epithelial surfaces by anchoring intermediate filaments to plasma membrane. These roles are best defined in cutaneous epithelium, but we previously identified lower levels of the desmosomal cadherins desmoglein-1 (DSG1) and desmocollin-1 (DSC1) and loss of barrier function in vaginal epithelium of mice treated systemically with the progestin depot medroxyprogesterone acetate (DMPA). We also showed these changes were avoided in mice treated with both DMPA and a conjugated equine estrogen vaginal cream. We extend these earlier results in the current investigation, identifying ephrin-A3 (EFNA3) as an important regulator of desmosomal cadherin gene expression in murine vaginal epithelial tissue. Moreover, topical treatment of mice with recombinant EFNA3 (rEFNA3) significantly increased vaginal expression of DSG1 and partially reversed the loss of vaginal epithelial barrier function induced by DMPA treatment. Consistent with this improvement in vaginal epithelial barrier protection, mortality caused by genital herpes simplex virus type 2 infection was delayed, but not prevented, in mice administered DMPA and rEFNA3 vs. DMPA alone. Together, current studies identify EFNA3 as a key regulator of desmosomal structure and function in vaginal epithelium and newly suggest that ephrin-Eph signaling pathways will provide an important target for enhancing vaginal epithelial integrity and barrier function.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1072-1081"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506861","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 : 2025-10-01Epub Date: 2025-06-27DOI: 10.1016/j.mucimm.2025.06.008
Bushra Alghamdi , Min Liu , Xin Huang , Rahul Debnath , Hamideh Afzali , Michael Troka , Akira Hasuike , Quinn Easter , Mi Zhou , Kevin Byrd , Michael Gonzalez , Kang I. Ko , Dana T. Graves
Poorly controlled diabetes significantly worsens periodontal disease, affecting millions worldwide, yet the mechanisms driving this destructive synergy remain unclear. We generated single-cell RNA sequencing profiles of diabetic periodontal tissue, revealing increased γδ T-cells, a loss of Tregs and greater neutrophil polarization as key mediators of diabetes-enhanced periodontitis. Flow cytometry confirmed significant expansion of IL-17A+ γδ+ T-cells and reduced Tregs in diabetic mice, with parallel findings of elevated CD3+IL-17A+ cells and reduced Tregs in human diabetic periodontal specimens. scRNAseq determined that diabetes caused a global increase in pro-inflammatory and a decrease in pro-resolving transcripts and enhanced inflammatory neutrophil polarization. Selective γδ T-cell inhibition reversed diabetes-enhanced periodontal destruction while minimally affecting normoglycemic controls and returned neutrophil infiltration to normoglycemic levels. These findings point to unique aspects of diabetes-induced dysregulation, implicate γδ T-cells as a driving factor and point to them as a potential therapeutic target in periodontitis and other diabetic complications.
{"title":"Single-cell RNA profiling identifies immune cell population shifts in diabetes associated mucosal inflammation","authors":"Bushra Alghamdi , Min Liu , Xin Huang , Rahul Debnath , Hamideh Afzali , Michael Troka , Akira Hasuike , Quinn Easter , Mi Zhou , Kevin Byrd , Michael Gonzalez , Kang I. Ko , Dana T. Graves","doi":"10.1016/j.mucimm.2025.06.008","DOIUrl":"10.1016/j.mucimm.2025.06.008","url":null,"abstract":"<div><div>Poorly controlled diabetes significantly worsens periodontal disease, affecting millions worldwide, yet the mechanisms driving this destructive synergy remain unclear. We generated single-cell RNA sequencing profiles of diabetic periodontal tissue, revealing increased γ<sup>δ</sup> T-cells, a loss of Tregs and greater neutrophil polarization as key mediators of diabetes-enhanced periodontitis. Flow cytometry confirmed significant expansion of IL-17A<sup>+</sup> γ<sup>δ+</sup> T-cells and reduced Tregs in diabetic mice, with parallel findings of elevated CD3<sup>+</sup>IL-17A<sup>+</sup> cells and reduced Tregs in human diabetic periodontal specimens. scRNAseq determined that diabetes caused a global increase in pro-inflammatory and a decrease in pro-resolving transcripts and enhanced inflammatory neutrophil polarization. Selective γ<sup>δ</sup> T-cell inhibition reversed diabetes-enhanced periodontal destruction while minimally affecting normoglycemic controls and returned neutrophil infiltration to normoglycemic levels. These findings point to unique aspects of diabetes-induced dysregulation, implicate γ<sup>δ</sup> T-cells as a driving factor and point to them as a potential therapeutic target in periodontitis and other diabetic complications.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1082-1097"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528986","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 : 2025-10-01Epub Date: 2025-07-16DOI: 10.1016/j.mucimm.2025.07.003
Jiaoyan Lv , Ziyan Su , Tao Wu , Yujie Tian , Xin Liu , Jiachen Liu , Xiaoguang Li , Wenlong Lai , Chen Dong , Li Wu
Alveolar macrophages (AMs) and dendritic cells (DCs) are the two major types of primary innate immune cells in allergic asthma and their functions were elaborately regulated during the progression of asthma. Tripartite motif-containing protein 33 (TRIM33) is a multifunctional protein that regulates differentiation and function of immune cells. However, its role in AMs and DCs in the context of allergic asthma remained unclear. Herein, we found that specific deletion of TRIM33 in AM and DCs (ItgaxCre-GFPTrim33fl/fl mice) affected their homeostasis in lung and induced aggravated allergic asthma. Though reduced in number in steady state, antigen-exposed Trim33−/− CD11b+ DCs exhibited comparable potency in triggering allergic asthma. Replacing Trim33−/− AMs with normal AMs could alleviate the aggravated HDM-induced airway inflammation and Th2 responses in ItgaxCre-GFPTrim33fl/fl mice. Moreover, Trim33−/− AMs exhibited stronger activation status and became an additional cellular source of CCL2 when encountered the allergen, thereby promoting the recruitment of CD11b+ DCs into lung and draining lymph nodes where they amplifying Th2 responses in ItgaxCre-GFPTrim33fl/fl mice. Our study revealed a crucial role of TRIM33 in controlling the aggravation of allergic asthma via repressing AM overactivation.
{"title":"TRIM33 prevents the exacerbation of allergic asthma by restricting the overactivation of alveolar macrophages","authors":"Jiaoyan Lv , Ziyan Su , Tao Wu , Yujie Tian , Xin Liu , Jiachen Liu , Xiaoguang Li , Wenlong Lai , Chen Dong , Li Wu","doi":"10.1016/j.mucimm.2025.07.003","DOIUrl":"10.1016/j.mucimm.2025.07.003","url":null,"abstract":"<div><div>Alveolar macrophages (AMs) and dendritic cells (DCs) are the two major types of primary innate immune cells in allergic asthma and their functions were elaborately regulated during the progression of asthma. Tripartite motif-containing protein 33 (TRIM33) is a multifunctional protein that regulates differentiation and function of immune cells. However, its role in AMs and DCs in the context of allergic asthma remained unclear. Herein, we found that specific deletion of TRIM33 in AM and DCs (<em>Itgax<sup>Cre-GFP</sup>Trim33<sup>fl/fl</sup></em> mice) affected their homeostasis in lung and induced aggravated allergic asthma. Though reduced in number in steady state, antigen-exposed <em>Trim33<sup>−/−</sup></em> CD11b<sup>+</sup> DCs exhibited comparable potency in triggering allergic asthma. Replacing <em>Trim33<sup>−/−</sup></em> AMs with normal AMs could alleviate the aggravated HDM-induced airway inflammation and Th2 responses in <em>Itgax<sup>Cre-GFP</sup>Trim33<sup>fl/fl</sup></em> mice. Moreover, <em>Trim33<sup>−/−</sup></em> AMs exhibited stronger activation status and became an additional cellular source of CCL2 when encountered the allergen, thereby promoting the recruitment of CD11b<sup>+</sup> DCs into lung and draining lymph nodes where they amplifying Th2 responses in <em>Itgax</em><sup>Cre-GFP</sup><em>Trim33</em><sup>fl/fl</sup> mice. Our study revealed a crucial role of TRIM33 in controlling the aggravation of allergic asthma via repressing AM overactivation.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1159-1170"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668045","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 : 2025-10-01Epub Date: 2025-07-22DOI: 10.1016/j.mucimm.2025.07.007
Joey Ming Er Lim , Sabrina Ottolini , Shou Kit Hang , Martin Daniel Qui , Adeline Chia , Jenny Guek Hong Low , Nina Le Bert , Anthony Tanoto Tan , Antonio Bertoletti
The nasal cavity is the entry site for respiratory viruses. Understanding how the nasal cavity sustains memory CD8+ T cell is essential for improving respiratory virus management and vaccine development. Here, we sampled CD8+ T cells from the upper nasal turbinate and peripheral blood of healthy adults. We analysed their transcriptomic profile and antigen specificity for respiratory (SARS-CoV-2, Influenza A) and non-respiratory (HCMV) viruses.
Transcriptomic analysis revealed that nasal CD8+ T cells failed to upregulate STAT1 following TCR stimulation, potentially enabling clonal expansion despite the antiproliferative effects of IFN signalling. They also exhibited a cytotoxic, Th1-like profile with tissue-residency markers but lacked TCF7 expression, suggesting limited self-renewal capacity. The CD8+ T cell analysis of antigen specificity demonstrates that local nasal exposure is indispensable for virus-specific CD8+ T cell detection. Only SARS-CoV-2 and influenza-specific but not HCMV-specific CD8+ T cells were detected in the nasal compartment. However, their persistence over time in the nasal cavity appears linked to repetitive viral exposure.
Our findings provide insights into the adaptations of nasal-resident CD8+ T cells and highlight challenges in eliciting durable nasal T cell immunity, with important implications for vaccine strategies against respiratory pathogens.
{"title":"Dynamics of virus-specific CD8+ T cells in the human nasal cavity","authors":"Joey Ming Er Lim , Sabrina Ottolini , Shou Kit Hang , Martin Daniel Qui , Adeline Chia , Jenny Guek Hong Low , Nina Le Bert , Anthony Tanoto Tan , Antonio Bertoletti","doi":"10.1016/j.mucimm.2025.07.007","DOIUrl":"10.1016/j.mucimm.2025.07.007","url":null,"abstract":"<div><div>The nasal cavity is the entry site for respiratory viruses. Understanding how the nasal cavity sustains memory CD8+ T cell is essential for improving respiratory virus management and vaccine development. Here, we sampled CD8+ T cells from the upper nasal turbinate and peripheral blood of healthy adults. We analysed their transcriptomic profile and antigen specificity for respiratory (SARS-CoV-2, Influenza A) and non-respiratory (HCMV) viruses.</div><div>Transcriptomic analysis revealed that nasal CD8+ T cells failed to upregulate STAT1 following TCR stimulation, potentially enabling clonal expansion despite the antiproliferative effects of IFN signalling. They also exhibited a cytotoxic, Th1-like profile with tissue-residency markers but lacked TCF7 expression, suggesting limited self-renewal capacity. The CD8+ T cell analysis of antigen specificity demonstrates that local nasal exposure is indispensable for virus-specific CD8+ T cell detection. Only SARS-CoV-2 and influenza-specific but not HCMV-specific CD8+ T cells were detected in the nasal compartment. However, their persistence over time in the nasal cavity appears linked to repetitive viral exposure.</div><div>Our findings provide insights into the adaptations of nasal-resident CD8+ T cells and highlight challenges in eliciting durable nasal T cell immunity, with important implications for vaccine strategies against respiratory pathogens.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1218-1227"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708144","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 : 2025-10-01Epub Date: 2025-07-26DOI: 10.1016/j.mucimm.2025.07.006
Samuel Alvarez-Arguedas , Khadijah Mazhar , Andi Wangzhou , Ishwarya Sankaranarayanan , Gabriela Gaona , John T. Lafin , Ron B. Mitchell , Theodore J. Price , Michael U. Shiloh
The nasal, oropharyngeal, and bronchial mucosa are primary contact points for airborne pathogens like Mycobacterium tuberculosis (Mtb), SARS-CoV-2, and influenza virus. While mucosal surfaces can function as both entry points and barriers to infection, mucosa-associated lymphoid tissues (MALT) facilitate early immune responses to mucosal antigens. MALT contains a variety of specialized epithelial cells, including a rare cell type called a microfold cell (M cell) that functions to transport apical antigens to basolateral antigen-presenting cells, a crucial step in the initiation of mucosal immunity. M cells have been extensively characterized in the gastrointestinal (GI) tract in murine and human models. However, the precise development and functions of human airway M cells are unknown. Here, using single-nucleus RNA sequencing (snRNA-seq), we generated an atlas of cells from the human adenoid and identified 26 unique cell types representing basal, club, hillock, and hematopoietic lineages, defined their developmental trajectories, and determined cell-cell relationships. Using trajectory analysis, we found that human airway M cells develop from progenitor club cells and express a gene signature distinct from intestinal M cells. Surprisingly, we also identified a heretofore unknown epithelial cell type demonstrating a robust interferon-stimulated gene signature. Our analysis of human adenoid cells enhances our understanding of mucosal immune responses and the role of M cells in airway immunity. This work also provides a resource for understanding early interactions of pathogens with airway mucosa and a platform for development of mucosal vaccines.
{"title":"Single cell transcriptional analysis of human adenoids identifies molecular features of airway microfold cells","authors":"Samuel Alvarez-Arguedas , Khadijah Mazhar , Andi Wangzhou , Ishwarya Sankaranarayanan , Gabriela Gaona , John T. Lafin , Ron B. Mitchell , Theodore J. Price , Michael U. Shiloh","doi":"10.1016/j.mucimm.2025.07.006","DOIUrl":"10.1016/j.mucimm.2025.07.006","url":null,"abstract":"<div><div>The nasal, oropharyngeal, and bronchial mucosa are primary contact points for airborne pathogens like <em>Mycobacterium tuberculosis</em> (Mtb), SARS-CoV-2, and influenza virus. While mucosal surfaces can function as both entry points and barriers to infection, mucosa-associated lymphoid tissues (MALT) facilitate early immune responses to mucosal antigens. MALT contains a variety of specialized epithelial cells, including a rare cell type called a microfold cell (M cell) that functions to transport apical antigens to basolateral antigen-presenting cells, a crucial step in the initiation of mucosal immunity. M cells have been extensively characterized in the gastrointestinal (GI) tract in murine and human models. However, the precise development and functions of human airway M cells are unknown. Here, using single-nucleus RNA sequencing (snRNA-seq), we generated an atlas of cells from the human adenoid and identified 26 unique cell types representing basal, club, hillock, and hematopoietic lineages, defined their developmental trajectories, and determined cell-cell relationships. Using trajectory analysis, we found that human airway M cells develop from progenitor club cells and express a gene signature distinct from intestinal M cells. Surprisingly, we also identified a heretofore unknown epithelial cell type demonstrating a robust interferon-stimulated gene signature. Our analysis of human adenoid cells enhances our understanding of mucosal immune responses and the role of M cells in airway immunity. This work also provides a resource for understanding early interactions of pathogens with airway mucosa and a platform for development of mucosal vaccines.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1199-1217"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732357","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 : 2025-10-01Epub Date: 2025-07-01DOI: 10.1016/j.mucimm.2025.06.011
Daichi Nonaka , Soichiro Yoshida , Kenta Nakano , Xiaojun Li , Tadashi Okamura , Eiji Umemoto , Taisho Yamada , Miyuki Watanabe , Shozo Jinno , Minako Ito , Makoto Tsuda , Naoto Noguchi , Jean X Jiang , Eriko Sumiya , Shinichiro Sawa
Macrophages play essential roles in immune defense and tissue homeostasis, but the mechanisms underlying their colonization in the gut mucosa remain incompletely understood. Here, we identify CSF1, primarily derived from fibroblasts, as the dominant factor maintaining mucosal macrophage colonization, whereas IL-34 deficiency alone has a minimal impact. We reveal that CSF1R ligands originate from distinct cellular sources: macrophages at the upper villus region depend on fibroblast-derived CSF1 and IL-34, while macrophages in the lower villus and the submucosal (lower villus + SM) region are regulated by CSF1 from both fibroblasts and endothelial cells. Additionally, within the lower villus + SM region, CSF1-producing CD81+ LepR+ fibroblasts directly interact with CD163+ macrophages, forming a localized niche. The loss of CSF1 in fibroblasts results in accelerated systemic dissemination of Salmonella Typhimurium, highlighting fibroblast-derived CSF1 as a key regulator of gut macrophage function in host defense. Collectively, our findings uncover a previously unrecognized fibroblast-macrophage crosstalk that governs gut macrophage homeostasis and immunity.
{"title":"Fibroblast-derived CSF1 maintains colonization of gut mucosal macrophage to resist bacterial infection","authors":"Daichi Nonaka , Soichiro Yoshida , Kenta Nakano , Xiaojun Li , Tadashi Okamura , Eiji Umemoto , Taisho Yamada , Miyuki Watanabe , Shozo Jinno , Minako Ito , Makoto Tsuda , Naoto Noguchi , Jean X Jiang , Eriko Sumiya , Shinichiro Sawa","doi":"10.1016/j.mucimm.2025.06.011","DOIUrl":"10.1016/j.mucimm.2025.06.011","url":null,"abstract":"<div><div>Macrophages play essential roles in immune defense and tissue homeostasis, but the mechanisms underlying their colonization in the gut mucosa remain incompletely understood. Here, we identify CSF1, primarily derived from fibroblasts, as the dominant factor maintaining mucosal macrophage colonization, whereas IL-34 deficiency alone has a minimal impact. We reveal that CSF1R ligands originate from distinct cellular sources: macrophages at the upper villus region depend on fibroblast-derived CSF1 and IL-34, while macrophages in the lower villus and the submucosal (lower villus + SM) region are regulated by CSF1 from both fibroblasts and endothelial cells. Additionally, within the lower villus + SM region, CSF1-producing CD81<sup>+</sup> LepR<sup>+</sup> fibroblasts directly interact with CD163<sup>+</sup> macrophages, forming a localized niche. The loss of CSF1 in fibroblasts results in accelerated systemic dissemination of <em>Salmonella</em> Typhimurium, highlighting fibroblast-derived CSF1 as a key regulator of gut macrophage function in host defense. Collectively, our findings uncover a previously unrecognized fibroblast-macrophage crosstalk that governs gut macrophage homeostasis and immunity.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1113-1123"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560556","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}
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