Mucosal Immunology最新文献

{"title":"Airway macrophage glycolysis controls lung homeostasis and responses to aeroallergen","authors":"Gesa J. Albers ,&nbsp;Christina Michalaki ,&nbsp;Patricia P. Ogger ,&nbsp;Amy F. Lloyd ,&nbsp;Benjamin Causton ,&nbsp;Simone A. Walker ,&nbsp;Anna Caldwell ,&nbsp;John M. Halket ,&nbsp;Linda V. Sinclair ,&nbsp;Sarah H. Forde ,&nbsp;Cormac McCarthy ,&nbsp;Timothy S.C. Hinks ,&nbsp;Clare M. Lloyd ,&nbsp;Adam J. Byrne","doi":"10.1016/j.mucimm.2024.10.002","DOIUrl":"10.1016/j.mucimm.2024.10.002","url":null,"abstract":"<div><div>The lungs represent a dynamic microenvironment where airway macrophages (AMs) are the major lung-resident macrophages. AMs dictate the balance between tissue homeostasis and immune activation and thus have contradictory functions by maintaining tolerance and tissue homeostasis, as well as initiating strong inflammatory responses. Emerging evidence has highlighted the connection between macrophage function and cellular metabolism. However, the functional importance of these processes in tissue-resident specialized macrophage populations such as those found in the airways, remain poorly elucidated. Here, we reveal that glycolysis is a fundamental pathway in AMs which regulates both lung homeostasis and responses to inhaled allergen. Using macrophage specific targeting <em>in vivo</em>, and multi-omics approaches, we determined that glycolytic activity in AMs is necessary to restrain type 2 (T2) immunity during homeostasis. Exposure to a range of common aeroallergens, including house dust mite (HDM), drove AM-glycolysis and furthermore, AM-specific inhibition of glycolysis altered inflammation in the airways and HDM-driven airway metabolic adaptations <em>in vivo</em>. Additionally, allergen sensitised asthmatics had profound metabolic changes in the airways, compared to non-sensitised asthmatic controls. Finally, we found that allergen driven AM-glycolysis in mice was TLR2 dependent. Thus, our findings demonstrate a direct relationship between glycolysis in AMs, AM-mediated homeostatic processes, and T2 immune responses in the lungs. These data suggest that glycolysis is essential for the plasticity of AMs. Depending on the immunological context, AM-glycolysis is required to exert homeostatic activity but once activated by allergen, AM-glycolysis influences inflammatory responses. Thus, precise modulation of glycolytic activity in AMs is essential for preserving lung homeostasis and regulating airway inflammation.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 121-134"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470338","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":"Activation of α2B/2C adrenergic receptor ameliorates ocular surface inflammation through enhancing regulatory T cell function","authors":"Nai-Wen Fan ,&nbsp;Man Yu ,&nbsp;Shudan Wang ,&nbsp;Tomas Blanco ,&nbsp;Zala Luznik ,&nbsp;Sunil K. Chauhan ,&nbsp;Veena Viswanath ,&nbsp;Daniel Gil ,&nbsp;Katherine Held ,&nbsp;Yihe Chen ,&nbsp;Reza Dana","doi":"10.1016/j.mucimm.2024.11.002","DOIUrl":"10.1016/j.mucimm.2024.11.002","url":null,"abstract":"<div><div>There is an unmet need for effectively treating dry eye disease (DED), a T cell-mediated chronic, inflammatory ocular surface disorder. Given the potential of nonneuronal adrenergic system in modulating T cell response, we herein investigated the therapeutic efficacy and the underlying mechanisms of a specific alpha 2 adrenergic receptor agonist (AGN-762, selective for α2B/2C receptor subtypes) in a mouse model of DED. Experimental DED was treated with the AGN-762 by oral gavage, either at disease induction or after disease establishment, and showed sustained amelioration, along with reduced expression of DED-pathogenic cytokines in ocular surface tissues, decreased corneal MHC-II⁺CD11b⁺ cells and lymphoid Th17 cells, and higher function of regulatory T cells (Treg). In vitro culture of DED-derived effector T helper cells (Teff) with AGN-762 failed to suppress Th17 response, while culture of DED-Treg with AGN-762 led to enhanced suppressive function of Treg and their IL-10 production. Adoptive transfer of AGN-762-pretreated DED-Treg in syngeneic B6.<em>Rag1^-/-</em> mice effectively suppressed DED Teff-mediated disease and Th17 response, and the effect was abolished by the neutralization of IL-10. In conclusion, our findings demonstrate that α2B/2C adrenergic receptor agonism effectively ameliorates persistent corneal epitheliopathy in DED by enhancing IL-10 production from Treg and thus restoring their immunoregulatory function.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 176-187"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622789","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":"Herpes stromal keratitis erodes the establishment of tissue-resident memory T cell pool in HSV-1 infected corneas","authors":"Mizumi Setia ,&nbsp;Pratima Krishna Suvas ,&nbsp;Mashidur Rana ,&nbsp;Anish Chakraborty ,&nbsp;Susmit Suvas","doi":"10.1016/j.mucimm.2024.11.003","DOIUrl":"10.1016/j.mucimm.2024.11.003","url":null,"abstract":"<div><div>The recurrent herpes simplex virus-1 (HSV-1) infection of the cornea can cause the development of herpes stromal keratitis (HSK). This chronic immunoinflammatory condition is a major cause of infection-induced vision loss. The previous episodes of HSK increase the risk of future recurrences in the same cornea. However, not all HSV-1 infected corneas that shed infectious virus at the ocular surface develop HSK, suggesting that corneal HSV-1 infection may cause an establishment of protective immunity in HSV-1 infected corneas. However, upon recurrent corneal HSV-1 infection, the established protective immunity can get compromised, resulting in the development of HSK. In this study, we compared the quantity and quality of tissue-resident memory T (T_RM) cells in HSV-1 infected corneas that did or did not develop HSK. Our results showed the predominance of T_RM cell in the epithelium than in stroma of HSV-1 infected corneas. Furthermore, HSV-1 infected non-HSK corneas exhibited more CD4 and CD8 T_RM cells than HSK corneas. The T_RM cells in non-HSK than in HSK corneas were more effective in clearing the infectious virus upon secondary corneal HSV-1 infection. Our results demonstrate the differential quantity and quality of T_RM cells in HSV-1 infected corneas that did or did not develop HSK.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 188-204"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710602","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 C-type lectin receptor MINCLE interferes with eosinophil function and protective intestinal immunity in Strongyloides ratti-infected mice","authors":"Lara Linnemann ,&nbsp;Jennifer Antwi-Ekwuruke ,&nbsp;Vinayaga Gnanapragassam ,&nbsp;Corinna Bang ,&nbsp;Malte Rühlemann ,&nbsp;Jürgen Ruland ,&nbsp;Wiebke Hartmann ,&nbsp;Lennart Heepmann ,&nbsp;Sara Dörken ,&nbsp;Saleh M. Yunus ,&nbsp;Birte Viebrock ,&nbsp;Annette Schlosser ,&nbsp;Bernd Lepenies ,&nbsp;Minka Breloer","doi":"10.1016/j.mucimm.2024.11.005","DOIUrl":"10.1016/j.mucimm.2024.11.005","url":null,"abstract":"<div><div><em>Strongyloides ratti</em> is a helminth parasite that displays tissue-migrating and intestinal life stages. Myeloid C-type lectin receptors (CLRs) are pattern recognition receptors that recognize pathogen-derived ligands and initiate immune responses. To date, the role of CLRs in <em>S. ratti</em> infection has not been investigated. Here, we show that <em>S. ratti</em>-derived ligands are recognized by the CLR Macrophage inducible Ca²⁺-dependent lectin receptor (MINCLE). While MINCLE-deficiency did not affect initiation of a protective anti-<em>S. ratti</em> type 2 immunity, MINCLE-deficient mice had a transient advantage in intestinal immunity. Unravelling the underlying mechanism, we show that next to macrophages, dendritic cells and neutrophils, a fraction of eosinophils express MINCLE and expand during <em>S. ratti</em> infection. MINCLE-deficient eosinophils exhibited a more active phenotype and prolonged expansion <em>in vivo</em> and displayed increased capacity to reduce <em>S. ratti</em> motility and produce reactive oxygen species <em>in vitro</em>, compared to wild-type (WT) eosinophils. Depletion of eosinophils in <em>S. ratti</em>-infected mice after the tissue-migration phase elevated intestinal worm burden in MINCLE-deficient mice to the WT level. Thus, our findings establish a central contribution of eosinophils to parasite ejection from the intestine and suggest that <em>S. ratti</em>-triggered signalling via MINCLE interferes with eosinophil mediated ejection of <em>S. ratti</em> from the intestine.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 220-231"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710607","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":"Combined plasma protein and memory T cell profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes","authors":"Maud Heredia ,&nbsp;Mohammed Charrout ,&nbsp;Renz C.W. Klomberg ,&nbsp;Martine A. Aardoom ,&nbsp;Maria M.E. Jongsma ,&nbsp;Polychronis Kemos ,&nbsp;Danielle H. Hulleman-van Haaften ,&nbsp;Bastiaan Tuk ,&nbsp;Lisette A. van Berkel ,&nbsp;Brenda Bley Folly ,&nbsp;Beatriz Calado ,&nbsp;Sandrine Nugteren ,&nbsp;Ytje Simons-Oosterhuis ,&nbsp;Michail Doukas ,&nbsp;Mathijs A. Sanders ,&nbsp;Gregory van Beek ,&nbsp;Frank M. Ruemmele ,&nbsp;Nicholas M. Croft ,&nbsp;Ahmed Mahfouz ,&nbsp;Marcel J.T. Reinders ,&nbsp;Janneke N. Samsom","doi":"10.1016/j.mucimm.2024.09.004","DOIUrl":"10.1016/j.mucimm.2024.09.004","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn’s disease, CD: <em>n</em> = 62; ulcerative colitis, UC: <em>n</em> = 20; age-matched controls <em>n</em> = 43), and after 10–12 weeks’ induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 76-89"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350418","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":"How the early life microbiome shapes immune programming in childhood asthma and allergies","authors":"Courtney Hoskinson,&nbsp;Charisse Petersen,&nbsp;Stuart E. Turvey","doi":"10.1016/j.mucimm.2024.12.005","DOIUrl":"10.1016/j.mucimm.2024.12.005","url":null,"abstract":"<div><div>Despite advances in our understanding of their diagnosis and treatment, pediatric allergies impose substantial burdens on affected children, families, and healthcare systems. Further, the prevalence of allergic diseases has dramatically increased over the past half-century, leading to additional concerns and concerted efforts to identify the origins, potential predictors and preventions, and therapies of allergic diseases. Together with the increase in allergic diseases, changes in lifestyle and early-life environmental influences have corresponded with changes in colonization patterns of the infant gut microbiome. The gut microbiome plays a key role in developing the immune system, thus greatly influencing the development of allergic disease. In this review, we specifically highlight the importance of the proper maturation and composition of the gut microbiome as an essential step in healthy child development or disease progression. By exploring the intertwined development of the immune system and microbiome across pediatric allergic diseases, we provide insights into potential novel strategies for their prevention and management.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 26-35"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829353","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":"Dissecting the metabolic signaling pathways by which microbial molecules drive the differentiation of regulatory B cells","authors":"Maik Luu ,&nbsp;Felix F Krause ,&nbsp;Heide Monning ,&nbsp;Anne Wempe ,&nbsp;Hanna Leister ,&nbsp;Lisa Mainieri ,&nbsp;Sarah Staudt ,&nbsp;Kai Ziegler-Martin ,&nbsp;Kira Mangold ,&nbsp;Nora Kappelhoff ,&nbsp;Yoav D Shaul ,&nbsp;Stephan Göttig ,&nbsp;Carlos Plaza-Sirvent ,&nbsp;Leon N Schulte ,&nbsp;Isabelle Bekeredjian-Ding ,&nbsp;Ingo Schmitz ,&nbsp;Ulrich Steinhoff ,&nbsp;Alexander Visekruna","doi":"10.1016/j.mucimm.2024.09.003","DOIUrl":"10.1016/j.mucimm.2024.09.003","url":null,"abstract":"<div><div>The host-microbiome axis has been implicated in promoting anti-inflammatory immune responses. Yet, the underlying molecular mechanisms of commensal-mediated IL-10 production by regulatory B cells (Bregs) are not fully elucidated. Here, we demonstrate that bacterial CpG motifs trigger the signaling downstream of TLR9 promoting IκB_NS-mediated expression of Blimp-1, a transcription regulator of IL-10. Surprisingly, this effect was counteracted by the NF-κB transcription factor c-Rel. A functional screen for intestinal bacterial species identified the commensal <em>Clostridium sporogenes</em>, secreting high amounts of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), as an amplifier of IL-10 production by promoting sustained mTOR signaling in B cells. Consequently, enhanced Breg functionality was achieved by combining CpG with the SCFA butyrate or the BCFA isovalerate thereby synergizing TLR- and mTOR-mediated pathways. Collectively, Bregs required two bacterial signals (butyrate and CpG) to elicit their full suppressive capacity and ameliorate T cell-mediated intestinal inflammation. Our study has dissected the molecular pathways induced by bacterial factors, which might contribute not only to better understanding of host-microbiome interactions, but also to exploration of new strategies for improvement of anti-inflammatory cellular therapy.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 66-75"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254726","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":"Dietary influence and immune balance: Regulating CD4+ IEL responses and MHCII in the gut","authors":"Jan Dobeš ,&nbsp;Tomáš Brabec","doi":"10.1016/j.mucimm.2024.12.011","DOIUrl":"10.1016/j.mucimm.2024.12.011","url":null,"abstract":"","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"18 1","pages":"Pages 36-38"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872586","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":"Deciphering the therapeutic potential of Myeloid-Specific JAK2 inhibition in acute respiratory distress syndrome","authors":"Shupei Gao ,&nbsp;Wenjuan Li ,&nbsp;Zhiwen Huang ,&nbsp;Jeffrey A. Deiuliis ,&nbsp;Zachary Braunstein ,&nbsp;Xinxin Liu ,&nbsp;Xinlu Li ,&nbsp;Mohammadreza Kosari ,&nbsp;Jun Chen ,&nbsp;Xinwen Min ,&nbsp;Handong Yang ,&nbsp;Quan Gong ,&nbsp;Zheng Liu ,&nbsp;Yingying Wei ,&nbsp;Ziyang Zhang ,&nbsp;Lingli Dong ,&nbsp;Jixin Zhong","doi":"10.1016/j.mucimm.2024.08.008","DOIUrl":"10.1016/j.mucimm.2024.08.008","url":null,"abstract":"<div><div>Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe inflammation and pulmonary dysfunction. Despite advancements in critical care, effective pharmacological interventions for ARDS remain elusive. While Janus kinase 2 (JAK2) inhibitors have emerged as an innovative treatment for numerous autoinflammatory diseases, their therapeutic potential in ARDS remains unexplored. In this study, we investigated the contribution of JAK2 and its underlying mechanisms in ARDS utilizing myeloid-specific JAK2 knockout murine models alongside a pharmacological JAK2 inhibitor. Notably, myeloid-specific JAK2 knockout led to a notable attenuation of ARDS induced by intratracheal administration of LPS, accompanied by reduced levels of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue. Intriguingly, the ameliorative effects were abolished upon the depletion of monocyte-derived alveolar macrophages (Mo-AMs) rather than tissue-resident alveolar macrophages (TR-AMs). JAK2 deficiency markedly reversed LPS-induced activation of STAT5 in macrophages. Remarkably, pharmacological JAK2 inhibition using baricitinib failed to substantially alleviate neutrophils infiltration, implying that specific inhibition of JAK2 in Mo-AMs is imperative for ARDS amelioration. Collectively, our data suggest that JAK2 may mitigate ARDS progression through the JAK2 pathway in Mo-AMs, underscoring JAK2 in alveolar macrophages, particularly Mo-AMs, as a promising therapeutic target for ARDS treatment.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1273-1284"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036439","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":"Distinct cell death pathways induced by granzymes collectively protect against intestinal Salmonella infection","authors":"Amanpreet Singh Chawla ,&nbsp;Maud Vandereyken ,&nbsp;Maykel Arias ,&nbsp;Llipsy Santiago ,&nbsp;Dina Dikovskaya ,&nbsp;Chi Nguyen ,&nbsp;Neema Skariah ,&nbsp;Nicolas Wenner ,&nbsp;Natasha B. Golovchenko ,&nbsp;Sarah J. Thomson ,&nbsp;Edna Ondari ,&nbsp;Marcela Garzón-Tituaña ,&nbsp;Christopher J. Anderson ,&nbsp;Megan Bergkessel ,&nbsp;Jay C. D. Hinton ,&nbsp;Karen L. Edelblum ,&nbsp;Julian Pardo ,&nbsp;Mahima Swamy","doi":"10.1016/j.mucimm.2024.08.006","DOIUrl":"10.1016/j.mucimm.2024.08.006","url":null,"abstract":"<div><div>Intestinal intraepithelial T lymphocytes (IEL) constitutively express high amounts of the cytotoxic proteases Granzymes (Gzm) A and B and are therefore thought to protect the intestinal epithelium against infection by killing infected epithelial cells. However, the role of IEL granzymes in a protective immune response has yet to be demonstrated. We show that GzmA and GzmB are required to protect mice against oral, but not intravenous, infection with <em>Salmonella enterica</em> serovar Typhimurium<em>,</em> consistent with an intestine-specific role. IEL-intrinsic granzymes mediate the protective effects by controlling intracellular bacterial growth and aiding in cell-intrinsic pyroptotic cell death of epithelial cells. Surprisingly, we found that both granzymes play non-redundant roles. <em>GzmB^-/-</em> mice carried significantly lower burdens of <em>Salmonella</em>, as predominant GzmA-mediated cell death effectively reduced bacterial translocation across the intestinal barrier. Conversely, in <em>GzmA^-/-</em> mice, GzmB-driven apoptosis favored luminal <em>Salmonella</em> growth by providing nutrients, while still reducing translocation across the epithelial barrier. Together, the concerted actions of both GzmA and GzmB balance cell death mechanisms at the intestinal epithelium to provide optimal control that <em>Salmonella</em> cannot subvert.</div></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":"17 6","pages":"Pages 1242-1255"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976178","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}