Discovery immunology最新文献

{"title":"PROS1 released by lung basal cells limits inflammation in epithelial and monocytes during SARS-CoV-2 infection.","authors":"Theodoros Simakou, Agnieszka M Szemiel, Lucy MacDonald, Karen Kerr, Domenico Somma, Katy Diallo, Jack Frew, Olympia M Hardy, Marcus Doohan, Aziza Elmesmari, Charles McSharry, Stefano Alivernini, Thomas D Otto, Arvind H Patel, Mariola Kurowska-Stolarska","doi":"10.1093/discim/kyaf012","DOIUrl":"10.1093/discim/kyaf012","url":null,"abstract":"<p><strong>Introduction: </strong>Factors regulating the severity of pneumonitis during viral infections remain unresolved. We previously found higher expression of protein S (PROS1) in lung epithelium of mild compared to severe coronavirus disease 2019 (COVID-19) patients. We hypothesized that PROS1 may protect the upper airways by regulating epithelial and myeloid cell responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.</p><p><strong>Methods: </strong>To test this, <i>in vitro</i> air-liquid interface (ALI) cultures of primary healthy human lung epithelial cells were infected with SARS-CoV-2. This model, validated through immunofluorescent staining, confocal microscopy, and single-cell RNA-sequencing, replicated pathogenic changes seen in the lungs of COVID-19. Regulation and secretion of PROS1, along with multiple soluble mediators, were quantified in control and infected cultures using ELISAs.</p><p><strong>Results: </strong>We found that PROS1 is present in the basal cells of healthy pseudostratified epithelium and is released during SARS-CoV-2 infection through an IFN-mediated process. Transcriptome analysis revealed that PROS1 downregulated the SARS-CoV-2-induced proinflammatory phenotypes of basal cells, transforming pathogenic CXCL10/11^high into a regenerative S100A2^posKRT^high basal cell phenotype. In parallel, SARS-CoV-2 increased the secretion of M-CSF from epithelial cells, which induced the expression of PROS1 receptor MERTK on monocytes interacting with the lung epithelium. PROS1, in turn, shifted SARS-CoV-2-induced pathogenic monocyte phenotypes toward a phenotype with increased MHC class II.</p><p><strong>Conclusion: </strong>These findings highlight the crucial role of PROS1 in protecting against severe lung pathology caused by SARS-CoV-2, by reducing epithelial- and monocyte-derived inflammation, promoting pro-repair epithelial phenotypes, and enhancing antigen presentation in myeloid cells.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"4 1","pages":"kyaf012"},"PeriodicalIF":0.0,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145115107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differentially expressed growth factors and cytokines drive phenotypic changes in transmissible cancers.","authors":"Kathryn G Maskell, Anna Schönbichler, Andrew S Flies, Amanda L Patchett","doi":"10.1093/discim/kyaf011","DOIUrl":"10.1093/discim/kyaf011","url":null,"abstract":"<p><strong>Introduction: </strong>The Tasmanian devil is threatened by two deadly transmissible Schwann cell cancers. A vaccine to protect Tasmanian devils from both devil facial tumour 1 (DFT1) and devil facial tumour 2 (DFT2), and improved understanding of the cancer cell biology, could support improved conservation actions.</p><p><strong>Methods: </strong>Previous transcriptomic analysis has implicated phenotypic cellular plasticity as a potential immune escape and survival mechanism of DFT1 cells. This phenotypic plasticity facilitates transition from a myelinating Schwann cell to a repair Schwann cell phenotype that exhibits mesenchymal characteristics. Here, we have identified cytokines and growth factors differentially expressed across DFT cell phenotypes and investigated their role in driving phenotypic plasticity and oncogenic properties of DFT cells.</p><p><strong>Results: </strong>Our results show that NRG1, IL16, TGFβ1, TGFβ2, and PDGFAA/AB proteins have significant and distinct effects on the proliferation rate, migratory capacity and/or morphology of DFT cells. Specifically, PDGFR signalling, induced by PDGFAA/AB, was a strong enhancer of cell proliferation and migration, while TGFβ1 and TGFβ2 induced epithelial-mesenchymal transition (EMT)-like changes, inhibited proliferation and increased migratory capacity.</p><p><strong>Conclusion: </strong>These findings suggest complex interactions between cytokine signalling, phenotypic plasticity, growth and survival of DFTs. Signalling pathways implicated in the propagation of DFT are potential targets for therapeutic intervention and vaccine development for Tasmanian devil conservation.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"4 1","pages":"kyaf011"},"PeriodicalIF":0.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Granulomatous inflammatory responses are elicited in the liver of PD-1 knockout mice by <i>de novo</i> genome mutagenesis.","authors":"","doi":"10.1093/discim/kyaf010","DOIUrl":"https://doi.org/10.1093/discim/kyaf010","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/discim/kyae018.].</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"4 1","pages":"kyaf010"},"PeriodicalIF":0.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spermidine suppresses DC activation via eIF5A hypusination and metabolic adaptation.","authors":"Gavin R Meehan, Utku Gunes, Larissa Camargo da Rosa, Hannah E Scales, George Finney, Ross Deehan, Sofia Sintoris, Aegli Athanasiadou, Jack Jones, Georgia Perona-Wright, James M Brewer","doi":"10.1093/discim/kyaf009","DOIUrl":"10.1093/discim/kyaf009","url":null,"abstract":"<p><strong>Introduction: </strong>Cell metabolism plays an important role in immune effector responses and through responding to metabolic signals, immune cells can adapt and regulate their function. Arginine metabolism in dendritic cells (DC) has been shown to reduce T cell activation; however, it is unclear how this immunosuppressive state is induced.</p><p><strong>Method: </strong>To address this issue, we examined the immunomodulatory capacity of various metabolites from arginine metabolism.</p><p><strong>Results: </strong>Through the use of a recently described DC:T cell interaction assay and flow cytometry we demonstrated that spermidine most significantly inhibited DC activation, preventing subsequent interactions with CD4 T cells. DC function could be restored by addition of inhibitors of spermidine metabolism via the eIF5A-hypusine axis, required for expression of some mitochondrial enzymes. We also demonstrated that the spermidine induced-immunosuppressive state protected DC against activation-induced loss of mitochondrial capacity for energy generation, which was also hypusination dependent.</p><p><strong>Conclusion: </strong>Taken together, these data demonstrate that spermidine is the key immunomodulatory component downstream of arginine metabolism and that it mediates this effect by stimulating hypusination-dependent protection of OXPHOS in DC, which in turn results in a reduced ability of DC to activate and interact with T cells. This pathway may be utilized by the immune system to regulate excessive immune responses but could also be exploited by pathogens as a method of immune evasion.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"4 1","pages":"kyaf009"},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation's impact on the interaction between oligodendrocytes and axons.","authors":"Tabitha R F Green, Marieke Pingen, Julia M Edgar","doi":"10.1093/discim/kyaf008","DOIUrl":"10.1093/discim/kyaf008","url":null,"abstract":"<p><p>Oligodendrocytes are responsible for the myelination of axons and providing trophic and metabolic support to the myelinated axon. They also interact with immune effector cells, including microglia and T cells, hence, are involved in central nervous system immune regulation. Given the crucial roles for oligodendrocytes and myelin in axonal function and maintenance, dysfunction, whether through cell death, myelin injury and loss, or failure in normal myelin formation, impairs neurological function. In diseases such as multiple sclerosis, the leukodystrophies, and viral infection, neuroinflammation is an important effector of myelin injury, having secondary consequences for the myelinated axon. In this review, we discuss the role of oligodendrocytes in health and inflammatory disease, with a focus on the interplay between inflammation and oligodendrocyte-axon interactions.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"4 1","pages":"kyaf008"},"PeriodicalIF":0.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The immunological role of oligodendrocytes: beyond myelin maintenance.","authors":"Juana M Pasquini, Jorge D Correale","doi":"10.1093/discim/kyaf005","DOIUrl":"10.1093/discim/kyaf005","url":null,"abstract":"<p><p>Oligodendrocytes (OGDs) are well-established cells in the central nervous system (CNS), primarily recognized for their role in myelination. However, emerging evidence suggests intrinsic differences among OGDs that may lead to diverse functions. OGDs heterogeneity could depend on their origin, location, age, and the presence of pathology. These variations indicate that specific populations of OGDs can modulate local immune responses and interact with other immune cells beyond their role in myelination. OGDs express major histocompatibility complex class I and class II molecules and can thus present endogenous and exogenous antigens to CD8 + and CD4 + T cells, respectively. In physiological conditions, OGDs release factors that maintain microglial quiescence and support homeostatic functions. However, during neuroinflammation, OGDs interact with microglia, astrocytes, and peripheral immune cells infiltrating the CNS, which may change their signaling profiles. In inflammatory conditions, OGDs demonstrate their active role in CNS immunology by producing a range of pro-inflammatory cytokines and chemokines. These factors are critical to the regulation of immune cell migration and activation within the CNS. Conversely, OGDs can also release anti-inflammatory factors, such as brain-derived neurotrophic factors, which help mitigate excessive inflammatory responses. Research into how OGDs affect and are affected by neighboring cells may unveil new therapeutic targets and strategies. The dual roles of OGDs in immunology and CNS function present both opportunities and challenges for advancing our understanding and treatment of CNS disorders.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"4 1","pages":"kyaf005"},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD28 and TCR differentially impact naïve and memory T cell responses.","authors":"Cayman Williams, Dalisay Giovacchini, Alan Kennedy, Neil Halliday, Erin Waters, Maximillian Robinson, Claudia Hinze, David M Sansom","doi":"10.1093/discim/kyaf006","DOIUrl":"10.1093/discim/kyaf006","url":null,"abstract":"<p><p>Manipulating CD28 co-stimulation is a key element of anti-tumour immune responses and treating autoimmune diseases. CD28 can reduce the T cell activation threshold but has a complex relationship with T cell receptor (TCR) signalling and an unclear role in specific T cell subsets. Using a series of <i>in vitro</i> stimulation assays, we have studied the relative contribution of CD28 and TCR signals in human CD4 + T cell responses. We show that not only the quantity of CD28 co-stimulation but also its intensity relative to TCR differentially impacts the division of naïve and memory T cells. We show that CD28 co-stimulation can have TCR-independent effects on memory T cell phenotype and cytokine production and in some settings can antagonize TCR-driven functions. These data highlight the complex relationship between CD28 co-stimulation and TCR signals and expose clear differences in their use by naïve and memory T cells.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"4 1","pages":"kyaf006"},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proliferation makes a substantive contribution to the maintenance of airway resident memory T-cell subsets in young pigs.","authors":"Eleni Vatzia, Yan Zhang, Ehsan Sedaghat-Rostami, Veronica Martini, Basudev Paudyal, Brigid Veronica Carr, Adam McNee, Chris Chiu, Katy Moffat, Becca Asquith, Peter Beverley, Derek Macallan, Elma Tchilian","doi":"10.1093/discim/kyaf007","DOIUrl":"10.1093/discim/kyaf007","url":null,"abstract":"<p><p>Tissue-resident memory (TRM) T cells play an important role in protection against respiratory infection but whether this memory is maintained by long-lived or dividing cells remains controversial. To address the rate of division of lung TRM T cells, deuterium-enriched water was administered orally to young pigs to label dividing lymphocytes. T-cell subsets were separated from blood, lymph nodes, and airways [bronchoalveolar lavage (BAL)], the latter comprising almost exclusively TRM. We show that, as in other species, circulating memory T-cell subsets divide more rapidly than naïve T cells. Rates of labelling of memory subsets were similar in blood and lymph nodes, consistent with the rapid and free exchange. Strikingly, the fraction of label in BAL was similar to those in blood/lymph nodes after 5-21 days of labelling, suggesting replacement with recently divided cells, but this was preceded at Day 2 by a phase when labelling was lower in BAL than blood/lymph node in some memory subsets. Our data exclude long-lived TRM as the source of BAL memory cells leaving three possible hypotheses: blood/airway exchange, <i>in situ</i> proliferation, or proliferation in the lung interstitium followed by migration to BAL. When considered in the context of other information, we favour the latter interpretation. These results indicate the dynamic nature of memory in the lung and have implications for harnessing immune responses against respiratory pathogens.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"4 1","pages":"kyaf007"},"PeriodicalIF":0.0,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic roles of ILC3 in endometrial repair and regeneration.","authors":"Antonia O Cuff, Ee Von Woon, Thomas Bainton, Brendan Browne, Phoebe M Kirkwood, Frances Collins, Douglas A Gibson, Philippa T K Saunders, Andrew W Horne, Mark R Johnson, David A MacIntyre, Victoria Male","doi":"10.1093/discim/kyaf004","DOIUrl":"https://doi.org/10.1093/discim/kyaf004","url":null,"abstract":"<p><strong>Background: </strong>Innate lymphoid cells (ILCs) are prominent in the human uterine mucosa and play physiological roles in pregnancy. ILC3 are the second-most common ILC subset in the uterine mucosa, but their role remains unclear.</p><p><strong>Methods: </strong>Here we define two subsets of lineage-negative CD56+ CD117+ CRTH2-uterine ILC3, distinguished by their expression of CD127.</p><p><strong>Results: </strong>The CD127- subset is most numerous and active during menstruation and immediately after parturition, suggesting a role in the repair of the uterine mucosa (called endometrium outside of pregnancy); the CD127+ subset is most numerous and active immediately after menstruation, as the endometrium regenerates. In healthy endometrium, ILC3 are spatially associated with glandular epithelial and endothelial cells, which both express receptors for the ILC3-derived cytokines, IL-22 and IL-8. In the eutopic endometrium of people with endometriosis, ILC3 are located further from glandular epithelial and endothelial cells suggesting that these cells may be less exposed to ILC3 products, potentially with negative consequences for endometrial regeneration.</p><p><strong>Conclusion: </strong>Our findings highlight the dynamic nature of ILC3 in the uterine mucosa and suggest their primary role is in repair and regeneration. An improved understanding of uterine ILC3 will inform future research on endometrial health and disease.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"4 1","pages":"kyaf004"},"PeriodicalIF":0.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Context matters: Immunology meets ecology.","authors":"Iris Mair, Kathryn J Else","doi":"10.1093/discim/kyaf003","DOIUrl":"10.1093/discim/kyaf003","url":null,"abstract":"","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":"4 1","pages":"kyaf003"},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}