Pub Date : 2025-10-01DOI: 10.1016/j.mucimm.2025.06.005
Sarah Sandford , Maximilien Evrard , Thomas N. Burn, Susan N. Christo, Marina H. Yakou, Andreas Obers, Yannick O. Alexandre, Laura K. Mackay, Scott N. Mueller
Numerous studies have shown that tissue-resident memory T (TRM) cells form in the intestine following pathogen clearance. However, most knowledge of intestinal TRM cells has derived from analyses restricted to the small intestine (SI). In contrast, less is known about TRM cell formation in the large intestine (LI). Here, we compared the abundance and phenotype of memory T cells across intestinal compartments. Using mouse models of infection, we observed that fewer memory T cells formed in the LI compared to the SI. Moreover, we found that T cells in the epithelium and lamina propria of the LI colon and caecum were phenotypically distinct from SI counterparts, comprising Ly6C-expressing CD8+ TRM cells with a distinct cytokine and granzyme profile. Using both loss- and gain-of-function approaches, we identified site-specific TGF-β dependencies, whereby Ly6C+CD103- TRM cells developed independently of TGF-β in both the SI and LI. In contrast, augmenting TGF-β signalling preferentially expanded Ly6C− TRM populations in the LI but not the SI, indicating that TGF-β signalling drives TRM cell heterogeneity between these compartments. Together, these findings underscore how regional differences in TRM cell responsiveness to local cues shape their development, phenotype, and function along the gastrointestinal tract.
{"title":"Memory T cell formation and phenotype varies across intestinal compartments","authors":"Sarah Sandford , Maximilien Evrard , Thomas N. Burn, Susan N. Christo, Marina H. Yakou, Andreas Obers, Yannick O. Alexandre, Laura K. Mackay, Scott N. Mueller","doi":"10.1016/j.mucimm.2025.06.005","DOIUrl":"10.1016/j.mucimm.2025.06.005","url":null,"abstract":"<div><div>Numerous studies have shown that tissue-resident memory T (T<sub>RM</sub>) cells form in the intestine following pathogen clearance. However, most knowledge of intestinal T<sub>RM</sub> cells has derived from analyses restricted to the small intestine (SI). In contrast, less is known about T<sub>RM</sub> cell formation in the large intestine (LI). Here, we compared the abundance and phenotype of memory T cells across intestinal compartments. Using mouse models of infection, we observed that fewer memory T cells formed in the LI compared to the SI. Moreover, we found that T cells in the epithelium and lamina propria of the LI colon and caecum were phenotypically distinct from SI counterparts, comprising Ly6C-expressing CD8<sup>+</sup> T<sub>RM</sub> cells with a distinct cytokine and granzyme profile. Using both loss- and gain-of-function approaches, we identified site-specific TGF-β dependencies, whereby Ly6C<sup>+</sup>CD103<sup>-</sup> T<sub>RM</sub> cells developed independently of TGF-β in both the SI and LI. In contrast, augmenting TGF-β signalling preferentially expanded Ly6C<sup>−</sup> <!-->T<sub>RM</sub> <!-->populations in the LI but not the SI, indicating that TGF-β signalling drives T<sub>RM</sub> <!-->cell heterogeneity between these compartments. Together, these findings underscore how regional differences in T<sub>RM</sub> cell responsiveness to local cues shape their development, phenotype, and function along the gastrointestinal tract.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1047-1057"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294133","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 : 2025-10-01DOI: 10.1016/j.mucimm.2025.06.006
Myoung Seung Kwon , Won Hyung Park , Jeongwoo La , Chae Won Kim , Heung Kyu Lee
Maternal exposure to environmental change during pregnancy is a critical determinant of offspring health and disease. Previous epidemiological studies have reported that maternal inflammation is linked to an increased incidence of postnatal allergy in offspring, although the underlying mechanisms remain largely unexplored. In this study, we employed a lipopolysaccharide-induced maternal inflammation murine model and found that offspring from dams with maternal immune activation (MIA) exhibited heightened allergic responses to house dust mite allergen. MIA offspring showed an increase in CD4+ T cell responses, which were mediated by increased T cell survival after activation, leading to promoting central and resident memory T cells formation. During maternal inflammation, TNF-α was identified as a crucial cytokine driving the heightened allergic response in offspring. TNF-α activates placental neutrophil, leading to placental necrosis. In parallel with placental damage, MIA offspring demonstrated increased glucocorticoid secretion in response to stress. Blockade of the glucocorticoid pathway during the sensitization phase mitigated the enhanced T cell memory response in MIA offspring, highlighting a mechanism by which maternal inflammation potentially modulates immune responses in offspring. Our findings elucidate one of the pathways by which maternal inflammation can influence postnatal immune regulation in offspring.
{"title":"Placental inflammation-driven T cell memory formation promotes allergic responses in offspring via endogenous glucocorticoids","authors":"Myoung Seung Kwon , Won Hyung Park , Jeongwoo La , Chae Won Kim , Heung Kyu Lee","doi":"10.1016/j.mucimm.2025.06.006","DOIUrl":"10.1016/j.mucimm.2025.06.006","url":null,"abstract":"<div><div>Maternal exposure to environmental change during pregnancy is a critical determinant of offspring health and disease. Previous epidemiological studies have reported that maternal inflammation is linked to an increased incidence of postnatal allergy in offspring, although the underlying mechanisms remain largely unexplored. In this study, we employed a lipopolysaccharide-induced maternal inflammation murine model and found that offspring from dams with maternal immune activation (MIA) exhibited heightened allergic responses to house dust mite allergen. MIA offspring showed an increase in CD4<sup>+</sup> T cell responses, which were mediated by increased T cell survival after activation, leading to promoting central and resident memory T cells formation. During maternal inflammation, TNF-α was identified as a crucial cytokine driving the heightened allergic response in offspring. TNF-α activates placental neutrophil, leading to placental necrosis. In parallel with placental damage, MIA offspring demonstrated increased glucocorticoid secretion in response to stress. Blockade of the glucocorticoid pathway during the sensitization phase mitigated the enhanced T cell memory response in MIA offspring, highlighting a mechanism by which maternal inflammation potentially modulates immune responses in offspring. Our findings elucidate one of the pathways by which maternal inflammation can influence postnatal immune regulation in offspring.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1058-1071"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302558","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 : 2025-10-01DOI: 10.1016/j.mucimm.2025.06.004
Maaike H. de Vries , Ewart W. Kuijk , Edward E.S. Nieuwenhuis
Intestinal epithelial cells need to be able to launch a quick and adequate immune response against pathogens, while tolerating commensals. This delicate balance requires a tight control over the activation of the NFκB and Interferon pathways to prevent chronic inflammation. Simultaneously, intestinal stem cell maintenance and differentiation are strictly regulated by the WNT/β-catenin and Bone Morphogenetic Protein signaling pathways to allow proper tissue homeostasis. There is emerging evidence that these cell identity and innate immunity pathways are molecularly intertwined, which may have implications for our mechanistic understanding of intestinal diseases such as inflammatory bowel disease and colorectal cancer. Here, we provide a comprehensive overview of the most important molecular interactions between these pathways. We identify the current gaps in our knowledge, and we propose promising areas for future research, in particular organoid research combined with single cell sequencing technologies.
{"title":"Innate immunity of the gut epithelium: Blowing in the WNT?","authors":"Maaike H. de Vries , Ewart W. Kuijk , Edward E.S. Nieuwenhuis","doi":"10.1016/j.mucimm.2025.06.004","DOIUrl":"10.1016/j.mucimm.2025.06.004","url":null,"abstract":"<div><div>Intestinal epithelial cells need to be able to launch a quick and adequate immune response against pathogens, while tolerating commensals. This delicate balance requires a tight control over the activation of the NFκB and Interferon pathways to prevent chronic inflammation. Simultaneously, intestinal stem cell maintenance and differentiation are strictly regulated by the WNT/β-catenin and Bone Morphogenetic Protein signaling pathways to allow proper tissue homeostasis. There is emerging evidence that these cell identity and innate immunity pathways are molecularly intertwined, which may have implications for our mechanistic understanding of intestinal diseases such as inflammatory bowel disease and colorectal cancer. Here, we provide a comprehensive overview of the most important molecular interactions between these pathways. We identify the current gaps in our knowledge, and we propose promising areas for future research, in particular organoid research combined with single cell sequencing technologies.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1005-1012"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285529","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 : 2025-10-01DOI: 10.1016/j.mucimm.2025.06.010
Anna A. Korchagina , Sergey A. Shein , Wayne T. Muraoka , Justin Nguyen , Qiangxing Chen , Anna A. Tumanova , Austin W. Todd , Carlos E. Rivera , Rita Tamayo , Paolo Casali , Ekaterina Koroleva , Alexei V. Tumanov
Patients with autoimmune diseases are more susceptible to foodborne infections, which can be exacerbated by immunosuppressive therapy. Tofacitinib, a JAK/STAT pathway inhibitor, was recently approved for the treatment of ulcerative colitis, yet its effects on the pathogenesis of intestinal infections remain unclear. Here, we examined the impact of oral tofacitinib treatment in a mouse model of Campylobacter jejuni (C. jejuni) infection. Our results show that early tofacitinib administration attenuates intestinal pathology without affecting bacterial colonization. Specifically, tofacitinib suppressed CXCL1, CXCL2, CCL2 chemokine expression by intestinal epithelial cells, limiting recruitment of monocytes and neutrophils to the gut. In addition, JAK/STAT inhibition reduced IFNγ-producing innate lymphoid cells (ILCs) and T cells in the gut. Furthermore, tofacitinib suppressed IFNγ production and ameliorated intestinal disease in humanized mice. Cell-fate mapping revealed that tofacitinib predominantly inhibited IFNγ production by NK1.1− ILCs derived from NKp46− progenitors and reduced NK1.1− ILC proliferation without affecting ILC3 to ILC1 plasticity. Notably, tofacitinib ameliorated intestinal disease even in the absence of T cells. These findings suggest that tofacitinib alleviates C. jejuni-induced colitis by reducing proinflammatory cytokine production by monocytes/macrophages/epithelial cells and suppressing IFNγ secretion by ILCs and T cells, while preserving antibacterial defenses.
{"title":"Tofacitinib ameliorates Campylobacter-induced intestinal pathology by suppressing IFNγ producing ILCs and T cells","authors":"Anna A. Korchagina , Sergey A. Shein , Wayne T. Muraoka , Justin Nguyen , Qiangxing Chen , Anna A. Tumanova , Austin W. Todd , Carlos E. Rivera , Rita Tamayo , Paolo Casali , Ekaterina Koroleva , Alexei V. Tumanov","doi":"10.1016/j.mucimm.2025.06.010","DOIUrl":"10.1016/j.mucimm.2025.06.010","url":null,"abstract":"<div><div>Patients with autoimmune diseases are more susceptible to foodborne infections, which can be exacerbated by immunosuppressive therapy. Tofacitinib, a JAK/STAT pathway inhibitor, was recently approved for the treatment of ulcerative colitis, yet its effects on the pathogenesis of intestinal infections remain unclear. Here, we examined the impact of oral tofacitinib treatment in a mouse model of <em>Campylobacter jejuni</em> (<em>C. jejuni</em>) infection. Our results show that early tofacitinib administration attenuates intestinal pathology without affecting bacterial colonization. Specifically, tofacitinib suppressed CXCL1, CXCL2, CCL2 chemokine expression by intestinal epithelial cells, limiting recruitment of monocytes and neutrophils to the gut. In addition, JAK/STAT inhibition reduced IFNγ-producing innate lymphoid cells (ILCs) and T cells in the gut. Furthermore, tofacitinib suppressed IFNγ production and ameliorated intestinal disease in humanized mice. Cell-fate mapping revealed that tofacitinib predominantly inhibited IFNγ production by NK1.1<sup>−</sup> ILCs derived from NKp46<sup>−</sup> progenitors and reduced NK1.1<sup>−</sup> ILC proliferation without affecting ILC3 to ILC1 plasticity. Notably, tofacitinib ameliorated intestinal disease even in the absence of T cells. These findings suggest that tofacitinib alleviates <em>C. jejuni</em>-induced colitis by reducing proinflammatory cytokine production by monocytes/macrophages/epithelial cells and suppressing IFNγ secretion by ILCs and T cells, while preserving antibacterial defenses.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1098-1112"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564969","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 : 2025-10-01DOI: 10.1016/j.mucimm.2025.07.002
Ahmed K. Kabil , Leo T. Liu , Chengxi Xu , Natalia Nayyar , Laura González , Sameeksha Chopra , Julyanne Brassard , Marie-Josée Beaulieu , Yicong Li , Ayaz Damji , Peter W. Zandstra , Marie-Renée Blanchet , Michael R. Hughes , Kelly M. McNagny
Advancements in vaccination and sanitation have significantly reduced the prevalence and burden of infectious diseases; however, these benefits have coincided with a marked rise in autoimmune and allergic disorders. Recent studies have investigated these linked trends through the lens of host–microbiome alterations, proposing these shifts as a potential explanatory mechanism. Previously, we demonstrated that vancomycin-induced depletion of short-chain fatty acid (SCFA) producing bacteria results in hyperactivation of ILC2s and exacerbated allergic responses. Here we investigate the effects of low-dose streptomycin on innate and adaptive immune cell populations and their activation states. Although streptomycin-treated mice exhibit normal allergic responses, they display heightened susceptibility to Th1/Th17-mediated disease, specifically hypersensitivity pneumonitis (HP). This is characterized by a two-fold increase in ILC3s and Th17 cells in the lungs, alongside activation of antigen-presenting cells (APCs) at steady state, an effect that is further amplified upon exposure to HP-inducing agents. Shotgun metagenomic analysis revealed that streptomycin-induced dysbiosis reduces microbial diversity, depletes bile acid–metabolizing bacteria, and enriches for metabolic pathways involved in branched-chain amino acid biosynthesis, including leucine, a known activator of mTORC1. Strikingly, administration of the secondary bile acid metabolite isolithocholic acid (an inverse agonist of RORγt), or an IL-23 neutralizing antibody, reverses the enhanced susceptibility to HP. Inhibition of mTORC1 also significantly reduced Th17/ILC3 responses and histopathology. Our findings underscore microbial equilibrium as a key determinant of susceptibility to HP and uncover a positive feedback loop between IL-23-producing APCs and ILC3/Th17 cells that mechanistically links dysbiosis to sustained type 3 inflammation; and we identify a simple, actionable means of intervention.
{"title":"Microbial dysbiosis sculpts a systemic ILC3/IL-17 axis governing lung inflammatory responses and central hematopoiesis","authors":"Ahmed K. Kabil , Leo T. Liu , Chengxi Xu , Natalia Nayyar , Laura González , Sameeksha Chopra , Julyanne Brassard , Marie-Josée Beaulieu , Yicong Li , Ayaz Damji , Peter W. Zandstra , Marie-Renée Blanchet , Michael R. Hughes , Kelly M. McNagny","doi":"10.1016/j.mucimm.2025.07.002","DOIUrl":"10.1016/j.mucimm.2025.07.002","url":null,"abstract":"<div><div>Advancements in vaccination and sanitation have significantly reduced the prevalence and burden of infectious diseases; however, these benefits have coincided with a marked rise in autoimmune and allergic disorders. Recent studies have investigated these linked trends through the lens of host–microbiome alterations, proposing these shifts as a potential explanatory mechanism. Previously, we demonstrated that <strong><em>vancomycin</em></strong>-induced depletion of short-chain fatty acid (SCFA) producing bacteria results in hyperactivation of ILC2s and exacerbated allergic responses. Here we investigate the effects of low-dose <strong><em>streptomycin</em></strong> on innate and adaptive immune cell populations and their activation states. Although streptomycin-treated mice exhibit normal allergic responses, they display heightened susceptibility to Th1/Th17-mediated disease, specifically hypersensitivity pneumonitis (HP). This is characterized by a two-fold increase in ILC3s and Th17 cells in the lungs, alongside activation of antigen-presenting cells (APCs) at steady state, an effect that is further amplified upon exposure to HP-inducing agents. Shotgun metagenomic analysis revealed that streptomycin-induced dysbiosis reduces microbial diversity, depletes bile acid–metabolizing bacteria, and enriches for metabolic pathways involved in branched-chain amino acid biosynthesis, including leucine, a known activator of mTORC1. Strikingly, administration of the secondary bile acid metabolite isolithocholic acid (an inverse agonist of RORγt), or an IL-23 neutralizing antibody, reverses the enhanced susceptibility to HP. Inhibition of mTORC1 also significantly reduced Th17/ILC3 responses and histopathology. Our findings underscore microbial equilibrium as a key determinant of susceptibility to HP and uncover a positive feedback loop between IL-23-producing APCs and ILC3/Th17 cells that mechanistically links dysbiosis to sustained type 3 inflammation; and we identify a simple, actionable means of intervention.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1139-1158"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691026","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 : 2025-10-01DOI: 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 : 2025-10-01DOI: 10.1016/j.mucimm.2025.07.001
Emilse Rodriguez , Constanza Savid-Frontera , Sofía C. Angiolini , María Luisa Hernáez-Sánchez , María Soledad Miró , María Estefania Viano , Paula A. Icely , Cinthia C. Stempin , María Cecilia Rodriguez-Galan , Concha Gil , Claudia E. Sotomayor
Vulvovaginal candidiasis (VVC) is a mucosal infection predominantly caused by Candida albicans, affecting over three-quarters of immunocompetent women worldwide. While the female genital tract mucosa is the primary defense against the fungus, the specific immune mechanisms involved in this host-pathogen interaction remain largely unknown. In this study, we explored the relevance of type-I interferons (IFNs-I) pathway using both in vitro and in vivo models of VVC. Our quantitative proteomic analysis revealed that C. albicans induces the activation of the IFNs-I pathway in human epithelial cells (ECs) of the female genital tract shortly after exposure to the fungus. Additionally, we identified β-glucans as a crucial fungal component involved in triggering this pathway. Using a VVC model in IFN-α/β receptor-deficient (Ifnar1-/-) mice, we demonstrated that IFNs-I regulate the fungal burden, C. albicans epithelial invasion, polymorphonuclear neutrophils (PMNs) recruitment, inflammatory tissue response, local cytokine balance, and the composition of T cell subsets in the draining lymph nodes. These findings underscore the pivotal role of the IFNs-I pathway in ECs-mediated responses against C. albicans, especially in the early stages of VVC development, offering insights into potential therapeutic targets for this condition.
{"title":"Type-I interferons in Vulvovaginal Candidiasis: Mechanism of epithelial early defense and immune regulation against Candida albicans","authors":"Emilse Rodriguez , Constanza Savid-Frontera , Sofía C. Angiolini , María Luisa Hernáez-Sánchez , María Soledad Miró , María Estefania Viano , Paula A. Icely , Cinthia C. Stempin , María Cecilia Rodriguez-Galan , Concha Gil , Claudia E. Sotomayor","doi":"10.1016/j.mucimm.2025.07.001","DOIUrl":"10.1016/j.mucimm.2025.07.001","url":null,"abstract":"<div><div>Vulvovaginal candidiasis (VVC) is a mucosal infection predominantly caused by <em>Candida albicans</em>, affecting over three-quarters of immunocompetent women worldwide. While the female genital tract mucosa is the primary defense against the fungus, the specific immune mechanisms involved in this host-pathogen interaction remain largely unknown. In this study, we explored the relevance of type-I interferons (IFNs-I) pathway using both <em>in vitro</em> and <em>in vivo</em> models of VVC. Our quantitative proteomic analysis revealed that <em>C. albicans</em> induces the activation of the IFNs-I pathway in human epithelial cells (ECs) of the female genital tract shortly after exposure to the fungus. Additionally, we identified β-glucans as a crucial fungal component involved in triggering this pathway. Using a VVC model in IFN-α/β receptor-deficient <em>(Ifnar1-/-)</em> mice, we demonstrated that IFNs-I regulate the fungal burden, <em>C. albicans</em> epithelial invasion, polymorphonuclear neutrophils (PMNs) recruitment, inflammatory tissue response, local cytokine balance, and the composition of T cell subsets in the draining lymph nodes. These findings underscore the pivotal role of the IFNs-I pathway in ECs-mediated responses against <em>C. albicans</em>, especially in the early stages of VVC development, offering insights into potential therapeutic targets for this condition.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 5","pages":"Pages 1124-1138"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619091","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 : 2025-10-01DOI: 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 : 2025-10-01DOI: 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}
Pub Date : 2025-10-01DOI: 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}
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