Cellular &Molecular Immunology最新文献

{"title":"Targeting pro-fibrotic macrophages with bioactive self-assembly peptides to retard kidney fibrosis – know thyself","authors":"Steven O’Reilly","doi":"10.1038/s41423-024-01194-2","DOIUrl":"10.1038/s41423-024-01194-2","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 8","pages":"935-937"},"PeriodicalIF":21.8,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Food restriction heals darkness-related second brain inflammation","authors":"Vinicius Kannen","doi":"10.1038/s41423-024-01196-0","DOIUrl":"10.1038/s41423-024-01196-0","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 8","pages":"938-940"},"PeriodicalIF":21.8,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue-resident memory T cells break tolerance to renal autoantigens and orchestrate immune-mediated nephritis","authors":"Frederic Arnold, Laurence Kupferschmid, Philipp Weissenborn, Lukas Heldmann, Jonas F. Hummel, Paulina Zareba,  Sagar, Manuel Rogg, Christoph Schell, Yakup Tanriver","doi":"10.1038/s41423-024-01197-z","DOIUrl":"10.1038/s41423-024-01197-z","url":null,"abstract":"Immune-mediated nephritis is a leading cause of acute kidney injury and chronic kidney disease. While the role of B cells and antibodies has been extensively investigated in the past, the advent of immune-checkpoint inhibitors has led to a reappraisal of the role of T cells in renal immunology. However, it remains elusive how T cells with specificity for renal autoantigens are activated and participate in immune-mediated nephritis. Here, we followed the fate and function of pathogen-activated autoreactive CD8 T cells that are specific for a renal autoantigen. We demonstrate that recently activated splenic CD8 T cells developed a hybrid phenotype in the context of renal autoantigen cross-presentation, combining hallmarks of activation and T cell dysfunction. While circulating memory T cells rapidly disappeared, tissue-resident memory T cells emerged and persisted within the kidney, orchestrating immune-mediated nephritis. Notably, T cells infiltrating kidneys of patients with interstitial nephritis also expressed key markers of tissue residency. This study unveils how a tissue-specific immune response can dissociate from its systemic counterpart driving a compartmentalized immune response in the kidneys of mice and man. Consequently, targeting tissue-resident memory T cells emerges as a promising strategy to control immune-mediated kidney disease.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 9","pages":"1066-1081"},"PeriodicalIF":21.8,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01197-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma","authors":"Yongchun Wang, Weibai Chen, Shuang Qiao, Hao Zou, Xing-juan Yu, Yanyan Yang, Zhixiong Li, Junfeng Wang, Min-shan Chen, Jing Xu, Limin Zheng","doi":"10.1038/s41423-024-01199-x","DOIUrl":"10.1038/s41423-024-01199-x","url":null,"abstract":"Metabolic changes play a crucial role in determining the status and function of macrophages, but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood. Here, we investigated the phenotype, contribution, and regulatory mechanisms of lipid droplet (LD)-laden macrophages (LLMs) in hepatocellular carcinoma (HCC). Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients. The LLMs displayed immunosuppressive phenotypes (with extensive expression of TREM2, PD-L1, CD206, and CD163) and attenuated the antitumor activities of CD8+ T cells. Mechanistically, tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages. LDs prolong LLM survival and promote CCL20 secretion, which further recruits CCR6+ Tregs to HCC tissue. Inhibiting LLM formation by targeting DGAT1 and DGAT2, which catalyze the synthesis of triglycerides, significantly reduced Treg recruitment, and delayed tumor growth in a mouse hepatic tumor model. Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 10","pages":"1120-1130"},"PeriodicalIF":21.8,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells","authors":"Bilal Alashkar Alhamwe, Viviane Ponath, Fahd Alhamdan, Bastian Dörsam, Clara Landwehr, Manuel Linder, Kim Pauck, Sarah Miethe, Holger Garn, Florian Finkernagel, Anna Brichkina, Matthias Lauth, Dinesh Kumar Tiwari, Malte Buchholz, Daniel Bachurski, Sabrina Elmshäuser, Andrea Nist, Thorsten Stiewe, Lisa Pogge von Strandmann, Witold Szymański, Vanessa Beutgen, Johannes Graumann, Julia Teply-Szymanski, Corinna Keber, Carsten Denkert, Ralf Jacob, Christian Preußer, Elke Pogge von Strandmann","doi":"10.1038/s41423-024-01195-1","DOIUrl":"10.1038/s41423-024-01195-1","url":null,"abstract":"Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV function, the EV-recipient cells, and their cellular response to EV uptake remain to be identified. Therefore, we studied the role of Bcl-2-associated-anthanogene 6 (BAG6), a regulator of EV biogenesis for cancer progression. We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment (TME) changes in mouse models for pancreatic ductal adenocarcinoma (PDAC) in a Bag6 pro- or deficient background. In vivo data were validated using mouse and human organoids and patient samples. Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release. Mechanistically, this was attributed to mast cell (MC) activation via EV-associated IL33. Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration. Tumor cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73. Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance. The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC. Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth. MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 8","pages":"918-931"},"PeriodicalIF":21.8,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"4-1BB-encoding CAR causes cell death via sequestration of the ubiquitin-modifying enzyme A20","authors":"Zhangqi Dou, Thomas Raphael Bonacci, Peishun Shou, Elisa Landoni, Mark G. Woodcock, Chuang Sun, Barbara Savoldo, Laura E. Herring, Michael J. Emanuele, Feifei Song, Albert S. Baldwin, Yisong Wan, Gianpietro Dotti, Xin Zhou","doi":"10.1038/s41423-024-01198-y","DOIUrl":"10.1038/s41423-024-01198-y","url":null,"abstract":"CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor (CAR) molecules play a critical role in promoting sustained antitumor activity of CAR-T cells. However, the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored. In the current study, we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling. Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity, cell aggregation via ICAM-1 overexpression, and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway. Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 8","pages":"905-917"},"PeriodicalIF":21.8,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the intestinal circadian clock by meal timing ameliorates gastrointestinal inflammation","authors":"Yunhui Niu, Marjolein Heddes, Baraa Altaha, Michael Birkner, Karin Kleigrewe, Chen Meng, Dirk Haller, Silke Kiessling","doi":"10.1038/s41423-024-01189-z","DOIUrl":"10.1038/s41423-024-01189-z","url":null,"abstract":"The expression of clock genes has been observed to be impaired in biopsies from patients with inflammatory bowel disease (IBD). Disruption of circadian rhythms, which occurs in shift workers, has been linked to an increased risk of gastrointestinal diseases, including IBD. The peripheral circadian clock in intestinal epithelial cells (IECs) was previously shown to balance gastrointestinal homeostasis by regulating the microbiome. Here, we demonstrated that the intestinal clock is disrupted in an IBD-relevant mouse model (IL-10−/−). A lack of the intestinal clock gene (Bmal1) in intestinal epithelial cells (IECs) in a chemically and a novel genetically induced colitis model (DSS, Bmal1IEC−/−xIL-10−/−) promoted colitis and dramatically reduced survival rates. Germ-free Bmal1IEC−/− mice colonized with disease-associated microbiota from IL-10−/− mice exhibited increased inflammatory responses, highlighting the importance of the local intestinal clock for microbiota-induced IBD development. Targeting the intestinal clock directly by timed restricted feeding (RF) in IL-10−/− mice restored intestinal clock functions, including immune cell recruitment and microbial rhythmicity; improved inflammatory responses; dramatically enhanced survival rates and rescued the histopathological phenotype. In contrast, RF failed to improve IBD symptoms in Bmal1IEC−/−xIL-10−/− mice, demonstrating the significance of the intestinal clock in determining the beneficial effect of RF. Overall, we provide evidence that intestinal clock dysfunction triggers host immune imbalance and promotes the development and progression of IBD-like colitis. Enhancing intestinal clock function by RF modulates the pathogenesis of IBD and thus could become a novel strategy to ameliorate symptoms in IBD patients.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 8","pages":"842-855"},"PeriodicalIF":21.8,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innate and adaptive immune responses that control lymph-borne viruses in the draining lymph node","authors":"Carolina R. Melo-Silva, Luis J. Sigal","doi":"10.1038/s41423-024-01188-0","DOIUrl":"10.1038/s41423-024-01188-0","url":null,"abstract":"The interstitial fluids in tissues are constantly drained into the lymph nodes (LNs) as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics. LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens. However, for lymph-borne viruses, which disseminate from the entry site to other tissues through the lymphatic system, immune cells in the draining LN (dLN) also play critical roles in curbing systemic viral dissemination during primary and secondary infections. Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells. Regardless of the entry mechanism, infected myeloid antigen-presenting cells, including various subtypes of dendritic cells, inflammatory monocytes, and macrophages, play a critical role in initiating the innate immune response within the dLN. This innate immune response involves cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons (IFN-Is) and other cytokines and recruit inflammatory monocytes and natural killer (NK) cells. IFN-I and NK cell cytotoxicity can restrict systemic viral spread during primary infections and prevent serious disease. Additionally, the memory CD8+ T-cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections. This review explores the intricate innate immune responses orchestrated within dLNs that contain primary viral infections and the role of memory CD8+ T-cells following secondary infection or CD8+ T-cell vaccination.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 9","pages":"999-1007"},"PeriodicalIF":21.8,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01188-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SENP6 restricts the IFN-I-induced signaling pathway and antiviral activity by deSUMOylating USP8","authors":"Jing Guo, Hui Zheng, Sidong Xiong","doi":"10.1038/s41423-024-01193-3","DOIUrl":"10.1038/s41423-024-01193-3","url":null,"abstract":"Type I interferon (IFN-I) exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections. In this study, we unveil SENP6 as a potent regulator of IFN-I antiviral activity. SENP6 does not impact the production of IFN-I induced by viruses but rather modulates IFN-I-activated signaling. Mechanistically, SENP6 constitutively interacts with USP8 and inhibits the SUMOylation of USP8, consequently restricting the interaction between USP8 and IFNAR2. The dissociation of USP8 from IFNAR2 enhances IFNAR2 ubiquitination and degradation, thus attenuating IFN-I antiviral activity. Correspondingly, the downregulation of SENP6 promotes the interaction between USP8 and IFNAR2, leading to a reduction in IFNAR2 ubiquitination and, consequently, an enhancement in IFN-I-induced signaling. This study deciphers a critical deSUMOylation-deubiquitination crosstalk that finely regulates the IFN-I response to viral infection.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 8","pages":"892-904"},"PeriodicalIF":21.8,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export","authors":"Saeed Daneshmandi, Qi Yan, Jee Eun Choi, Eriko Katsuta, Cameron R. MacDonald, Mounika Goruganthu, Nathan Roberts, Elizabeth A. Repasky, Prashant K. Singh, Kristopher Attwood, Jianmin Wang, Yosef Landesman, Philip L. McCarthy, Hemn Mohammadpour","doi":"10.1038/s41423-024-01187-1","DOIUrl":"10.1038/s41423-024-01187-1","url":null,"abstract":"Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 8","pages":"873-891"},"PeriodicalIF":21.8,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}