Mucosal Immunology最新文献

{"title":"Accumulation of mucosal and lymphoid hypo-functional granzyme K producing CD8+ effector memory T cells in idiopathic pulmonary fibrosis","authors":"Jetina Okereke,&nbsp;Andrew Craig,&nbsp;Michelle Rojas,&nbsp;Blake Degioanni,&nbsp;Allyson Lieberman,&nbsp;John Sembrat,&nbsp;John Evankovich,&nbsp;William Bain,&nbsp;Harinath Bahudhanapati,&nbsp;Daniel J. Kass,&nbsp;Jonathan K. Alder,&nbsp;Mark E. Snyder","doi":"10.1016/j.mucimm.2026.100387","DOIUrl":"10.1016/j.mucimm.2026.100387","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis is a progressive lung disease characterized by the rapid scarring of the lung parenchyma resulting in impaired gas exchange and early mortality. Current treatment options are limited; lung transplantation remains the only definitive treatment. The adaptive immune system has been increasingly evoked as a potential contributor to disease initiation or progression. Using spectral flow cytometry, immunofluorescence imaging, and in-vitro functional assays we studied T cells obtained from explanted lungs and lung draining lymph nodes (HLN) from patients with IPF and non-diseased controls. We found the accumulation of granzyme K producing, hypofunctional CD8⁺ T cells in the lungs and HLN from IPF compared to controls. We also showed the accumulation of regulatory T cells in both lung and HLN in patients with IPF. CD4⁺ and CD8⁺ T cells were found to accumulate around areas of active fibrosis in IPF lung sections. Finally, when exposed to extracellular granzyme K, epithelial cells from human lungs showed increased expression of genes related to fibrosis, proliferation, and inflammation. Together, these show that IPF lungs and lymph nodes are characterized by the accumulation of granzyme K producing T cells and that granzyme K can promote pro-fibrotic effects of lung epithelial cells, providing a potential means whereby T cells might contribute to lung fibrosis.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 5","pages":"Article 100387"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471304","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}

{"title":"Gut segmented filamentous Bacteria impedes growth of B16F10 subcutaneous tumors via modulating T cell function","authors":"Hirohito Abo,&nbsp;Seong-eun G. Kim,&nbsp;Vu L. Ngo,&nbsp;Michal P. Kuczma,&nbsp;Andrew T. Gewirtz","doi":"10.1016/j.mucimm.2026.100382","DOIUrl":"10.1016/j.mucimm.2026.100382","url":null,"abstract":"<div><div>Intestinal microbiota composition influences innate and adaptive immunity, both within and beyond the intestine. A prominent example of the latter is segmented filamentous bacteria (SFB), whose gut colonization reprograms alveolar macrophages (AM) and systemically shapes T cell polarity. We hypothesized that these impacts of SFB would influence anti-tumor immunity. We tested this hypothesis via intravenous and subcutaneous injection of B16F10 cells, which, respectively, models metastatic lung cancer and melanoma in mice. SFB colonization did not impact model lung cancer but suppressed melanoma growth and, concomitantly, prolonged survival. Such protection was completely lost in <em>Rag1</em>-deficient mice, indicating a requirement for adaptive immunity for the SFB-mediated tumor suppression. Concomitantly, SFB promoted infiltration of tumors by CD4⁺ and CD8⁺ T cells and, furthermore, enhanced their activation. The level of tumor suppression provided by SFB colonization was similar, but additive, to that conferred by immune checkpoint blockade. Thus, microbiota composition impacts T cell-mediated anti-tumor immunity in a site-specific manner. Mechanistic understanding of such interactions may inform cancer prevention and treatment.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 5","pages":"Article 100382"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422765","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}

{"title":"Single-cell RNA sequencing reveals intrinsic and microbiota-associated sex differences in murine lung","authors":"Alexandra Melton,&nbsp;Krista Ferrari,&nbsp;Joseph P. Hoffmann,&nbsp;Kejing Song,&nbsp;Jay K. Kolls,&nbsp;Janet E. McCombs","doi":"10.1016/j.mucimm.2026.100389","DOIUrl":"10.1016/j.mucimm.2026.100389","url":null,"abstract":"<div><div>Sex-based differences in respiratory disease outcomes are well recognized. However, the underlying immunological mechanisms driving this dimorphism remain incompletely understood. While sex hormones influence immune cell development and function, the role of commensal microbes in shaping sex-specific lung immunity has not been explored. Here, we used single-cell RNA sequencing (scRNAseq) and flow cytometry to profile lung immune cells in male and female mice housed under specific pathogen-free (SPF) or germ-free (GF) conditions. Under SPF conditions, males exhibited a striking myeloid bias, with increased monocytes and macrophages, along with broad upregulation of inflammatory mediators, including <em>S100a8, S100a9,</em> and <em>Il1b,</em> across multiple cell types, and enrichment of TNF and interferon (IFN) signaling pathways. In contrast, females displayed lymphocyte-skewed profiles, with higher frequencies of T cells, B cells, and natural killer (NK) cells. Interestingly, these sex-based differences in immune composition and inflammatory programs were largely absent in GF mice, suggesting that microbial exposure influences baseline immunological dimorphism between males and females. Notably, select sex-associated immune differences, including female-biased NK cell enrichment, persisted irrespective of microbial status, suggesting intrinsic, microbiota-independent programming. Together, these findings indicate that commensal microbes may modulate sex-specific lung immunity, potentially amplifying pre-existing intrinsic differences, highlighting the intersection of extrinsic (microbial) and intrinsic (sex-linked) factors in shaping baseline mucosal immunity.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 5","pages":"Article 100389"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579443","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}

{"title":"Enteric α-defensins contribute to intestinal mucosal immunity against SARS-CoV-2 infection","authors":"Yilin Yang,&nbsp;Qianxi Yang,&nbsp;Xin Huang,&nbsp;Chongbing Liao,&nbsp;Zhenguo Chen,&nbsp;Wuyuan Lu","doi":"10.1016/j.mucimm.2026.100392","DOIUrl":"10.1016/j.mucimm.2026.100392","url":null,"abstract":"<div><div>SARS-CoV-2 primarily targets epithelial cells in the respiratory and intestinal tracts where its cognate receptor ACE2 and obligate processing enzymes furin and TMPRSS2 are richly expressed. However, compared with severe inflammation and tissue damage in the lungs of a COVID-19 patient, clinical lesions in the intestine are rare, suggesting an effective intestinal mucosal immunity against SARS-CoV-2 infection. Here, we report that MMP7^−/−/hACE2 hybrid mice lacking mature enteric α-defensins or cryptdins were more susceptible to SARS-CoV-2 infection in the intestine than K18-hACE2 transgenic mice. The mouse α-defensin cryptdin-5 (Crp5) displayed potent and broad antiviral activity <em>in vitro</em> and <em>in vivo</em> by two distinct mechanisms, (1) directly targeting the RBD of the spike (S) protein to antagonize its interactions with ACE2, thus blocking viral attachment, membrane fusion and cell-to-cell transmission, and (2) binding to the 630 loop of the S protein to induce its multimerization, thereby impairing proteolytic processing, membrane fusion and, ultimately, viral infectivity. Our findings imply that enteric α-defensins help alleviate, as host protective factors, Covid-19 symptoms in the intestine despite higher ACE2 expression in the gut than in the lungs, and that Crp5 may be developed as a broad-spectrum antiviral for the treatment of coronavirus infection irrespective of virus type and variant.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 5","pages":"Article 100392"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148653977","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}

{"title":"Specialized pro-resolving mediators regulate in vitro human airway epithelial resistance to Aspergillus fumigatus","authors":"Khadeeja Adam Sy,&nbsp;Isabel Valsecchi,&nbsp;Maëlle Briottet,&nbsp;Marie Vaudin,&nbsp;Ellie-Flore Barny,&nbsp;Mohamed El Moustaphaoui,&nbsp;Françoise Botterel,&nbsp;Valérie Urbach","doi":"10.1016/j.mucimm.2026.100379","DOIUrl":"10.1016/j.mucimm.2026.100379","url":null,"abstract":"<div><div>Cystic fibrosis (CF) is caused by mutations in the <em>CFTR</em> gene resulting in alterations in the immune functions of the airway epithelium, including reduced biosynthesis of the specialized pro-resolving lipid mediators (SPMs). <em>Aspergillus fumigatus</em> is the most isolated filamentous fungus in patients with CF. This study explore whether specialized pro-resolving lipid mediators (SPMs) regulate the barrier function of airway epithelium in vitro during colonization by <em>A. fumigatus</em>. We have shown that mature <em>A. fumigatus</em> hyphae disrupt tight junctions in primary cultures of nasal epithelium from CF and non-CF patients, as well as in a CF bronchial epithelial cell line. However, these cellular models mount an immune response to resist the fungus. We found that epithelial vulnerability is strongly dependent on its initial level of differentiation and integrity at the time of fungal inoculation. Indeed, while highly differentiated and non-CF epithelia exhibit a strong resistance against <em>A. fumigatus</em> and a significant reduction in fungal load and hyphal growth, less differentiated epithelia have a limited capacity to maintain their structure and contain fungal growth. Furthermore, we have demonstrated the role of several SPMs that stimulate the innate immune response of the airway epithelium by preventing tight junction disruption induced by <em>A. fumigatus</em> colonization and decreasing fungal galactomannan secretion. Moreover, SPMs increase hBD2 transcription in highly differentiated nasal primary cultures from non-CF subjects, but not in those from CF patients, and these lipid mediators reduced the production of pro-inflammatory cytokines induced by fungal colonization. Overall, our data suggest that the reduction of SPMs in patients with CF could contribute to the difficulty of eradicating <em>A. fumigatus.</em> and this could open novel therapeutic perspectives to treat this disease.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 5","pages":"Article 100379"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405365","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}

{"title":"Mucosal BCG vaccination reprograms lung interstitial macrophages and enhances antimicrobial defense in mice","authors":"Aaron James Forde,&nbsp;Mara Esposito,&nbsp;Emanuela Kerschbamer,&nbsp;David Schreiner,&nbsp;Eduardo Moreo,&nbsp;Nikos Pantouloufos,&nbsp;Tiphaine M.N. Camarasa,&nbsp;Jean de Lima,&nbsp;Habiba Soliman,&nbsp;Maike Erber,&nbsp;Claire E. Depew,&nbsp;Wadschma Naderi,&nbsp;Carolyn G. King","doi":"10.1016/j.mucimm.2026.100391","DOIUrl":"10.1016/j.mucimm.2026.100391","url":null,"abstract":"<div><div>Bacille Calmette–Guérin (BCG) is the only licensed vaccine against tuberculosis (TB) but provides inconsistent protection against disease. Alveolar macrophages (AM) are widely considered the primary myeloid mediators of BCG-induced lung immunity, whereas the contribution of lung interstitial macrophages (IM) remains poorly defined. Here, we investigated pulmonary macrophage remodeling following BCG vaccination delivered by three distinct routes in mice, using flow cytometry, single cell RNA sequencing and spatial transcriptomics. We show that the route of vaccine administration dictates which macrophage subset is rewired. Intratracheal (IT) BCG preferentially reprograms IM, which form spatially organized immune hubs with CD4 T cells, while AM retain a transcriptional state closer to homeostasis. In contrast, intravenous (IV) BCG induces transcriptional remodeling of AM. Importantly, IT BCG conferred superior protection against both <em>Mycobacterium tuberculosis</em> and the heterologous pathogen <em>Pseudomonas aeruginosa</em>. Collectively, these findings identify IM as key mediators of mucosal vaccine-induced protection and highlight macrophage subset targeting as a framework for optimizing vaccines against respiratory pathogens.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 5","pages":"Article 100391"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148592762","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}

{"title":"The club cell circadian clock regulates temporal patterns in leukocyte trafficking in chronic allergic airways disease","authors":"Jafar Cain,&nbsp;Amlan Chakraborty,&nbsp;Vishvangi Deugi,&nbsp;Karolina Krakowiak,&nbsp;David A. Bechtold,&nbsp;Julie E. Gibbs,&nbsp;Hannah J. Durrington","doi":"10.1016/j.mucimm.2026.100384","DOIUrl":"10.1016/j.mucimm.2026.100384","url":null,"abstract":"<div><div>Patients with allergic asthma exhibit distinct temporal variations in symptoms and disease severity, which oscillate across the 24 h day. We have previously shown that the molecular circadian clock plays a critical role in temporally gating the response to allergen challenge in mice. Club cells, a subset of pulmonary bronchial epithelial cells, are implicated in the gating of time-dependent responses to type-1 inflammatory stimuli and trafficking of neutrophils to the lung. Using a club cell specific <em>Bmal1</em> knockout mouse (CCSP<em>-Bmal1</em> KO) we found that this is also true in the setting of chronic type-2 pulmonary inflammation, where eosinophil and T-helper 2 cell trafficking patterns were abolished in mice lacking a functional circadian clock within the lung. Notably, we find that circadian patterns in airway permeability are lost in CCSP<em>-Bmal1</em> KO mice, rendering the barrier equally permissible to trafficking cells at all times of day.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 5","pages":"Article 100384"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620803","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}

{"title":"4-1BBL on monocyte lineage cells rather than on classical dendritic cells drives CD8+ T cell accumulation in the respiratory tract and protects from severe respiratory influenza infection","authors":"Karen K.M. Yeung,&nbsp;Seungwoo Lee,&nbsp;Nathalia V. Batista,&nbsp;Razieh Eshraghisamani,&nbsp;Tianning Yu,&nbsp;Tobias M. Hohl,&nbsp;Tania H. Watts","doi":"10.1016/j.mucimm.2026.100374","DOIUrl":"10.1016/j.mucimm.2026.100374","url":null,"abstract":"<div><div>Seasonal epidemics and the persistent threat of a pandemic provide a strong impetus to understand mechanisms of protection against influenza infection. T cell intrinsic signaling through the TNFR superfamily member 4-1BB is critical for the accumulation of antigen-specific CD8⁺ effector and memory T cells in the lung and protection from influenza A virus (IAV). However, the APCs that provide 4-1BB ligand (4-1BBL) have not been definitively characterized. Here, using single-cell RNA sequencing and multiparameter flow cytometry, we define murine monocyte lineage cell (MC) and classical dendritic cell (cDC) populations in the lung during acute IAV infection and show that 4-1BBL is more highly expressed on CD64⁺MAR-I⁺CD26⁻ inflammatory MCs than on MHCII^hiCD11c⁺CD26⁺ cDCs following IAV infection. Mixed bone marrow chimeras, in which 4-1BBL is only absent on Ccr2-dependent cells, and Cre-driven deletion using <em>Ccr2</em>- or <em>Zbtb46-cre</em> demonstrate that 4-1BBL on MCs rather than cDCs is important for the accumulation of nucleoprotein (NP)-specific CD8⁺ effector and tissue-resident memory T cells. Importantly, 4-1BBL on Ccr2-dependent cells is critical for mouse survival following severe IAV infection. These findings reveal a division of labor between cDC and MCs, with infMCs uniquely providing 4-1BBL to increase CD8⁺ T cell accumulation in the lung and protect against severe IAV infection.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 5","pages":"Article 100374"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369279","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}

{"title":"Dysregulated MUC5B and MUC5AC impair epithelial barrier function and alter granulocyte frequency and activation in the lung and distal sites","authors":"Neeraj Patil,&nbsp;Jonas Ambjörnsson,&nbsp;Sofia Kallin,&nbsp;Duaa Malla,&nbsp;Hiba Sayedali,&nbsp;Emilia Åkesson,&nbsp;Madeleine Rådinger,&nbsp;Gunnar C. Hansson,&nbsp;Kristina Johansson","doi":"10.1016/j.mucimm.2026.100385","DOIUrl":"10.1016/j.mucimm.2026.100385","url":null,"abstract":"<div><h3>Background</h3><div>Mucus obstructs the airways in respiratory diseases where MUC5B is the major gel-forming mucin in COPD and MUC5AC-rich mucus dominates in asthma. Mucin production changes in response to inflammatory signals, but whether mucin dysregulation drives inflammation is less studied.</div></div><div><h3>Objective</h3><div>We sought to identify if MUC5B and MUC5AC affect immune cell composition during homeostasis and inflammation.</div></div><div><h3>Methods</h3><div>Immune cells in airways and distal compartments from wild type (WT), <em>Muc5ac</em>^−/− and <em>Muc5b</em>^−/− mice were assessed by flow cytometry and morphological examination. Epithelial permeability was assessed via intranasal dextran administration, and inflammation was induced by IL-33. Gene expression and inflammatory mediators were analyzed by qPCR and ELISA, respectively.</div></div><div><h3>Results</h3><div>Mucin expression increased with age in WT mice, where <em>Muc5b</em> remained 40 times more abundant than <em>Muc5ac</em>, however, single-mucin deficiency resulted in compensatory increase of the other. MUC5B protected mice from increased bacterial load with neutrophil infiltration in airways, but MUC5B and MUC5AC were similarly important to prevent eosinophilia in lungs and distal compartments. Airway inflammation correlated with epithelial shedding, aberrant expression of epithelial integrity genes, increased epithelial permeability, and altered alarmins along with activation of innate lymphoid cells upon mucin disruption. Finally, IL-33 airway challenge increased <em>Muc5b</em> and <em>Muc5ac</em> where both mucins were required for normal granulocyte recruitment to lungs.</div></div><div><h3>Conclusion</h3><div>MUC5B and MUC5AC play nonredundant yet complementary roles in maintaining airway immune homeostasis and regulating inflammation. Loss or imbalance of either mucin disrupts normal epithelial responses and compromises barrier integrity, potentially driving downstream changes in immune cell composition locally and systemically. It highlights an underappreciated immunomodulatory function of airway mucus which sheds new light on its role in asthma and COPD.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 5","pages":"Article 100385"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497793","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}

{"title":"Helminths hijack the TGFβ receptor to promote a pro-regenerative program in the intestinal stem cell compartment","authors":"Danielle Karo-Atar,&nbsp;Kaitlin A. Olsen,&nbsp;Tamar Eliahu,&nbsp;Adi Asculai,&nbsp;Blanca E. Callejas,&nbsp;Susan Westfall,&nbsp;Holden Teslak,&nbsp;Joshua W. Lee,&nbsp;Julia Czubik,&nbsp;Loick Joumier,&nbsp;Nathalie Croteau,&nbsp;Ghislaine Fontes,&nbsp;Marc Parisien,&nbsp;Luda Diatchenko,&nbsp;Mohan Malleshaiah,&nbsp;Jean-François Trempe,&nbsp;Alex Gregorieff,&nbsp;Simon A. Hirota,&nbsp;Irah L. King","doi":"10.1016/j.mucimm.2026.100372","DOIUrl":"10.1016/j.mucimm.2026.100372","url":null,"abstract":"<div><div>The intestine is a multifunctional tissue relying on multipotent stem cells to establish a repertoire of epithelial cell lineages. We have previously shown that the enteric parasitic nematode <em>Heligmosomoides polygyrus bakeri</em> (<em>Hpb</em>) directly regulates the intestinal stem cell compartment, tuning the epithelium to a regenerative fetal-like state, marked by the expansion of Clusterin-expressing revival stem cells (revSCs) and inhibiting goblet and tuft cell differentiation. However, the host signaling pathway driving this response remained obscure. Here, we demonstrate that TGFβ receptor (TGFβR) engagement is critical for helminth-induced epithelial reprogramming. Specifically, we show that <em>Hpb</em> induces potent epithelial TGFβR signaling in both mouse and human intestinal epithelium and that <em>Hpb</em>-mediated revSC expansion is TGFβR-dependent. In addition, we show that the loss of TGFβR signaling in the intestinal epithelium enhances goblet cell expansion while compromising <em>Hpb</em> egg production. Finally, we identify the TGFβ mimic, TGM, as the <em>Hpb</em>-secreted protein responsible for the induction of the fetal-like transcriptional program and revSC expansion. Collectively, our study reveals how a parasitic helminth hijacks epithelial TGFβR signaling to expand a pro-regenerative stem cell population and support host-helminth mutualism.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"19 5","pages":"Article 100372"},"PeriodicalIF":5.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376303","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}