Nature ImmunologyPub Date : 2025-09-15DOI: 10.1038/s41590-025-02276-7
Carlson Tsui, Leonie Heyden, Lifen Wen, Catarina Gago da Graça, Nikita Potemkin, Aleksej Frolov, Daniel Rawlinson, Lei Qin, Verena C. Wimmer, Marjan Hadian-Jazi, Darya Malko, Chun-Hsi Su, Sining Li, Kayla R. Wilson, Helena Horvatic, Sharanya K. Wijesinghe, Marcela L. Moreira, Lachlan Dryburgh, Dominik Schienstock, Lisa Rausch, Daniel T. Utzschneider, Cornelia Halin, Scott N. Mueller, Marc D. Beyer, Sammy Bedoui, Zeinab Abdullah, Jan Schröder, Axel Kallies
{"title":"Lymph nodes fuel KLF2-dependent effector CD8+ T cell differentiation during chronic infection and checkpoint blockade","authors":"Carlson Tsui, Leonie Heyden, Lifen Wen, Catarina Gago da Graça, Nikita Potemkin, Aleksej Frolov, Daniel Rawlinson, Lei Qin, Verena C. Wimmer, Marjan Hadian-Jazi, Darya Malko, Chun-Hsi Su, Sining Li, Kayla R. Wilson, Helena Horvatic, Sharanya K. Wijesinghe, Marcela L. Moreira, Lachlan Dryburgh, Dominik Schienstock, Lisa Rausch, Daniel T. Utzschneider, Cornelia Halin, Scott N. Mueller, Marc D. Beyer, Sammy Bedoui, Zeinab Abdullah, Jan Schröder, Axel Kallies","doi":"10.1038/s41590-025-02276-7","DOIUrl":"10.1038/s41590-025-02276-7","url":null,"abstract":"Exhausted CD8+ T (TEX) cell responses are maintained by precursors of exhausted T (TPEX) cells that possess high self-renewal and developmental potential. TPEX cells also drive the proliferative burst of effector T cells upon therapeutic immune checkpoint blockade (ICB). However, the spatial context and signals that regulate their differentiation and function are not well defined. Here we identify developmental and functional compartmentalization of TPEX and TEX cells across secondary lymphoid organs during chronic infection. We show that stem-like CD62L+ TPEX and effector-like CX3CR1+ TEX cells constitute a distinct developmental lineage that is promoted by the lymph node (LN) microenvironment and dependent on the transcription factor KLF2. LNs act as a niche in which migratory dendritic cells provide antigen and costimulatory signals to maintain the proliferative fitness of CD62L+ TPEX cells and generation of CX3CR1+ TEX cells. Moreover, LNs exclusively drive the proliferative burst and systemic dissemination of CX3CR1+ TEX cells during ICB. Thus, our findings identify a unique role for LNs in the maintenance of T cell differentiation and function during systemic chronic infection and ICB therapy. Here the authors show a function for lymph nodes in the maintenance of effector T cell differentiation and function during chronic infection and checkpoint blockade, identifying a spatial component in the regulation of exhausted T cell fitness.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1752-1765"},"PeriodicalIF":27.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059695","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}
Nature ImmunologyPub Date : 2025-09-15DOI: 10.1038/s41590-025-02280-x
Jianhui Sun, Jun Yang, Jie Tao, Yifan Yang, Rui Wang, Huacai Zhang, Wenyi Liu, Shulin Zhao, Runze Shao, Yuhui He, Shaolin Tao, Yaxiong Li, Hai Qu, Di Liu, Jingwen Li, Jianxin Jiang, Bo Deng, Chu Gao, Ping Lin, Ling Zeng, Ping Meng, Gan Wang
{"title":"Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response","authors":"Jianhui Sun, Jun Yang, Jie Tao, Yifan Yang, Rui Wang, Huacai Zhang, Wenyi Liu, Shulin Zhao, Runze Shao, Yuhui He, Shaolin Tao, Yaxiong Li, Hai Qu, Di Liu, Jingwen Li, Jianxin Jiang, Bo Deng, Chu Gao, Ping Lin, Ling Zeng, Ping Meng, Gan Wang","doi":"10.1038/s41590-025-02280-x","DOIUrl":"10.1038/s41590-025-02280-x","url":null,"abstract":"The formation of membrane pores by cleaved N-terminal gasdermin D (GSDMD-NT) results in the release of cytokines and inflammatory cell death, known as pyroptosis. Blocking GSDMD-NT pores is an attractive and promising strategy for mitigating inflammation. Here we demonstrate that SK56, an artificial intelligence-screened peptide, effectively obstructs GSDMD-NT pores and inhibits pyroptosis and cytokine release in macrophages and human peripheral blood leukocyte-induced pyroptosis. SK56 prevents septic death induced by lipopolysaccharide or cecal ligation and puncture surgery in mice. SK56 does not influence cleavage of interleukin-1β or GSDMD. Instead, SK56 inhibits the release of cytokines from pyroptotic macrophages, mitigates the activation of primary mouse dendritic cells triggered by incubation with pyroptotic cytomembranes and prevents widespread cell death of human alveolar organoids in an organoid–macrophage coculture model. SK56 blocks GSDMD-NT pores on lipid-bilayer nanoparticles and enters pyroptotic macrophages to inhibit mitochondrial damage. SK56 presents new therapeutic possibilities for counteracting inflammation, which is implicated in numerous diseases. Wang and colleagues show that an AI-assisted designed peptide obstructs GSDMD pores and inhibits IL-1β and IL-18 release and pyroptosis.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1660-1672"},"PeriodicalIF":27.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02280-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059694","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}
Nature ImmunologyPub Date : 2025-09-15DOI: 10.1038/s41590-025-02268-7
Augusto Faria Andrade, Romain Sigaud, Evan Puligandla, Bridget Liu, Elham Karimi, Alva Annett, Morteza Rezanejad, Wajih Jawhar, Robert Taylor, Yi Cao, Simone Schmid, Florian Selt, Pablo Hernáiz Driever, Svea Horn, Philipp Sievers, Marco Prinz, Markus Glatzel, Christian Mawrin, Christian Hartmann, Camelia-Maria Monoranu, Liza Konnikova, Felix Sahm, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Arend Koch, Claudia L. Kleinman, David Capper, Logan Walsh, Nada Jabado, Till Milde
{"title":"A spatial map of MAPK-activated immunosuppressive myeloid populations in pediatric low-grade glioma","authors":"Augusto Faria Andrade, Romain Sigaud, Evan Puligandla, Bridget Liu, Elham Karimi, Alva Annett, Morteza Rezanejad, Wajih Jawhar, Robert Taylor, Yi Cao, Simone Schmid, Florian Selt, Pablo Hernáiz Driever, Svea Horn, Philipp Sievers, Marco Prinz, Markus Glatzel, Christian Mawrin, Christian Hartmann, Camelia-Maria Monoranu, Liza Konnikova, Felix Sahm, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Arend Koch, Claudia L. Kleinman, David Capper, Logan Walsh, Nada Jabado, Till Milde","doi":"10.1038/s41590-025-02268-7","DOIUrl":"10.1038/s41590-025-02268-7","url":null,"abstract":"Pediatric low-grade gliomas (pLGGs) are mitogen-activated protein kinase (MAPK) pathway-activated brain tumors prevalent in children and are associated with morbidity despite favorable survival. Here using imaging mass cytometry, we spatially characterized at the single-cell level the tumor microenvironment (TME) of 120 pLGG cases, considering age, molecular drivers, brain location and tumor subtype. Our analysis identified myeloid cells—including resident microglia and bone marrow-derived macrophages—as the predominant immune population in the TME, particularly in optic pathway tumors. Additionally, we discovered an immune signature predictive of progression-free survival. Spatial analysis identified specific cellular interactions, notably myeloid–myeloid contacts and macrophage-enriched regions harboring MAPK-activated, TIM-3+ myeloid cells, suggesting an immunosuppressive TME. Our study provides a comprehensive resource on the immune landscape of these pLGGs and underscores the immunosuppressive role of diverse myeloid infiltrates. These findings also indicate that combining TIM-3 blockade with MAPK inhibition might be a promising therapeutic strategy to target both the TME and oncogenic MAPK activation in pLGG tumors. Here the authors spatially map human pediatric low-grade gliomas using imaging mass cytometry, focusing on immunosuppressive myeloid cell populations and their functionality in tumor–immune interactions and tumor progression.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1794-1806"},"PeriodicalIF":27.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059692","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}
Nature ImmunologyPub Date : 2025-09-11DOI: 10.1038/s41590-025-02270-z
David Granadier, Kirsten Cooper, Dante Acenas II, Anastasia Kousa, Makya Warren, Vanessa Hernandez, Lorenzo Iovino, Paul deRoos, Emma E. Lederer, Steve Shannon-Sevillano, Sinéad Kinsella, Cindy Evandy, Marcel R. M. van den Brink, Andri Lemarquis, Jarrod A. Dudakov
{"title":"Damage-induced IL-18 stimulates thymic NK cells limiting endogenous tissue regeneration","authors":"David Granadier, Kirsten Cooper, Dante Acenas II, Anastasia Kousa, Makya Warren, Vanessa Hernandez, Lorenzo Iovino, Paul deRoos, Emma E. Lederer, Steve Shannon-Sevillano, Sinéad Kinsella, Cindy Evandy, Marcel R. M. van den Brink, Andri Lemarquis, Jarrod A. Dudakov","doi":"10.1038/s41590-025-02270-z","DOIUrl":"10.1038/s41590-025-02270-z","url":null,"abstract":"Interleukin-18 (IL-18) is an acute-phase proinflammatory molecule crucial for mediating viral clearance by activating T helper 1 CD4+ T cells, cytotoxic CD8+ T cells and natural killer (NK) cells. Here, we show that mature IL-18 is generated in the thymus following numerous distinct forms of tissue damage, all of which cause caspase-1-mediated immunogenic cell death. We report that IL-18-stimulated cytotoxic NK cells limit endogenous thymic regeneration, a critical process that ensures the restoration of immune competence after acute insults such as stress, infection, chemotherapy and radiation. NK cells suppress thymus recovery by aberrantly targeting thymic epithelial cells, which act as the master regulators of organ function and regeneration. Together, our data reveal a new pathway regulating tissue regeneration in the thymus and suggest IL-18 as a potential therapeutic target to boost thymic function. Moreover, given the enthusiasm for IL-18 as a cancer immunotherapy due to its capacity to elicit a type 1 immune response, these findings also offer insight into potential off-target effects. The thymus is sensitive to acute insults including infection, as well as to injury from chemotherapy and myeloablative conditioning before hematopoietic cell transplantation. Here, Granadier et al. describe a role for IL-18 in limiting thymic regeneration by stimulating NK cells, which then target thymic epithelial cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1699-1711"},"PeriodicalIF":27.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02270-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032200","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}
Nature ImmunologyPub Date : 2025-09-10DOI: 10.1038/s41590-025-02287-4
{"title":"T cells engineered to target a shared β-catenin mutation eradicate solid tumors in mice","authors":"","doi":"10.1038/s41590-025-02287-4","DOIUrl":"10.1038/s41590-025-02287-4","url":null,"abstract":"We identified T cell receptors (TCRs) targeting antigenic peptides that contain a shared β-catenin mutation (CTNNB1S37F) presented on common human leukocyte antigen alleles. TCR-engineered T cells eliminated patient-derived tumors and prevented relapse in vivo in mice, highlighting a strategy to exploit public neoantigens for TCR-based immunotherapy in solid cancers.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1641-1642"},"PeriodicalIF":27.6,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025471","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}
Nature ImmunologyPub Date : 2025-09-09DOI: 10.1038/s41590-025-02258-9
Lennard Dalit, Chin Wee Tan, Amania A. Sheikh, Ryan Munnings, Lauren J. Howson, Carolina Alvarado, Tabinda Hussain, Aidil Zaini, Lucy Cooper, Alana Kirn, Lauren Hailes, Angela Nguyen, Bailey E. Williams, Ming Z. M. Zheng, Carolien E. van de Sandt, Laura K. Mackay, Katie L. Flanagan, Katherine Kedzierska, Nicola Harris, Jennifer A. Juno, Colby Zaph, Nicole L. La Gruta, Melissa J. Davis, Stephen L. Nutt, Kim L. Good-Jacobson, Vanessa L. Bryant, Joanna R. Groom
{"title":"Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity","authors":"Lennard Dalit, Chin Wee Tan, Amania A. Sheikh, Ryan Munnings, Lauren J. Howson, Carolina Alvarado, Tabinda Hussain, Aidil Zaini, Lucy Cooper, Alana Kirn, Lauren Hailes, Angela Nguyen, Bailey E. Williams, Ming Z. M. Zheng, Carolien E. van de Sandt, Laura K. Mackay, Katie L. Flanagan, Katherine Kedzierska, Nicola Harris, Jennifer A. Juno, Colby Zaph, Nicole L. La Gruta, Melissa J. Davis, Stephen L. Nutt, Kim L. Good-Jacobson, Vanessa L. Bryant, Joanna R. Groom","doi":"10.1038/s41590-025-02258-9","DOIUrl":"10.1038/s41590-025-02258-9","url":null,"abstract":"CD4+ T follicular helper (TFH) cells support tailored B cell responses against multiple classes of pathogens. To reveal how diverse TFH phenotypes are established, we profiled mouse TFH cells in response to viral, helminth and bacterial infection. We identified a core TFH signature that is distinct from CD4+ T follicular regulatory and effector cells and identified pathogen-specific transcriptional modules that shape TFH function. Cytokine-transcriptional TFH programming demonstrated that type I interferon and TGFβ signaling direct individual TFH phenotypes to instruct B cell output. Cytokine-directed TFH transcriptional phenotypes are shared within human germinal centers, but distinct TFH phenotypes dominate between donors and following immune challenge or in antibody-mediated disease. Finally, we identified new cell surface markers that align with distinct TFH phenotypes. Thus, we provide a comprehensive resource of TFH diversity in humans and mice to enable immune monitoring during infection and disease and to inform the development of context-specific vaccines. Dalit, Tan and colleagues provide a multiomic profile of T follicular helper (TFH) cells responses to diverse pathogens, revealing a blueprint for transcriptional flexibility and new tools to interrogate TFH heterogeneity in mice and humans.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1821-1835"},"PeriodicalIF":27.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02258-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017499","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}
Nature ImmunologyPub Date : 2025-09-09DOI: 10.1038/s41590-025-02278-5
{"title":"Bacterial toxins rewire the trans-Golgi network to activate the inflammatory response","authors":"","doi":"10.1038/s41590-025-02278-5","DOIUrl":"10.1038/s41590-025-02278-5","url":null,"abstract":"Cholesterol-dependent cytolysins produced by diverse bacterial pathogens are internalized by host cells and translocate to the trans-Golgi network (TGN). They remodel the TGN into a platform for assembly of the NLRP3 inflammasome, a crucial innate immune signaling pathway in host defense and pro-inflammatory diseases.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1639-1640"},"PeriodicalIF":27.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017495","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}
Nature ImmunologyPub Date : 2025-09-08DOI: 10.1038/s41590-025-02263-y
Emma C. Erlich, Quazim A. Alayo, Ayoung Kim, Jichang Han, Rachel L. Mintz, Christopher G. Huckstep, Heather S. Ruiz, Rachael L. Field, Taylor J. Dunning, Leila S. Saleh, Mark H. Hoofnagle, Alexei V. Tumanov, Farshid Guilak, Jonathan R. Brestoff, Rafael S. Czepielewski, Gwendalyn J. Randolph
{"title":"Distinct roles for B cell-derived LTα3 and LTα1β2 in TNF-mediated ileitis","authors":"Emma C. Erlich, Quazim A. Alayo, Ayoung Kim, Jichang Han, Rachel L. Mintz, Christopher G. Huckstep, Heather S. Ruiz, Rachael L. Field, Taylor J. Dunning, Leila S. Saleh, Mark H. Hoofnagle, Alexei V. Tumanov, Farshid Guilak, Jonathan R. Brestoff, Rafael S. Czepielewski, Gwendalyn J. Randolph","doi":"10.1038/s41590-025-02263-y","DOIUrl":"10.1038/s41590-025-02263-y","url":null,"abstract":"Crohn’s disease pathology is modeled in TNFΔARE+/− mice that overproduce tumor necrosis factor (TNF) to drive disease through TNF receptors. An alternative ligand for TNF receptors, soluble LTα3, is produced by B cells, but has received scarce attention because LTα also partners with LTβ to generate membrane-tethered LTαβ2 that promotes tertiary lymphoid tissue—another feature of Crohn’s disease. We hypothesized that B cell-derived LTαβ2 would critically affect ileitis in TNFΔARE+/− mice. However, whereas deleting LTβ in B cells was essential for tertiary lymphoid tissue, disease pathology was minimally affected. By contrast, loss of B cell-derived LTα increased intestinal permeability, shrunk the pool of IgA+ ileal plasma cells, elevated cytokines and prompted weight loss, including loss of muscle mass—a systemic feature of Crohn’s disease. Neutralizing antibodies to LTα3 strongly augmented the cachexic-like effects of TNF. Thus, B cell-produced LTαβ2 and LTα3 have distinct roles in ileitis, with the role of LTα3 unexpectedly protective through counterbalancing TNF. Erlich et al. show that soluble LTα and membrane-bound LTα1β2 lymphotoxins expressed by B cells play distinct roles to attenuate the pathology observed in ileitis.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1781-1793"},"PeriodicalIF":27.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41590-025-02263-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009042","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}
Nature ImmunologyPub Date : 2025-09-05DOI: 10.1038/s41590-025-02293-6
Rebeca Arroyo Hornero, Raul A. Maqueda-Alfaro, Miguel A. Solís-Barbosa, Rebecca A. Leylek, Olin Medina Chavez, Olivia M. Martinez, Andres Gottfried-Blackmore, Juliana Idoyaga
{"title":"Publisher Correction: TNF and type I interferon crosstalk controls the fate and function of plasmacytoid dendritic cells","authors":"Rebeca Arroyo Hornero, Raul A. Maqueda-Alfaro, Miguel A. Solís-Barbosa, Rebecca A. Leylek, Olin Medina Chavez, Olivia M. Martinez, Andres Gottfried-Blackmore, Juliana Idoyaga","doi":"10.1038/s41590-025-02293-6","DOIUrl":"https://doi.org/10.1038/s41590-025-02293-6","url":null,"abstract":"<p>Correction to: <i>Nature Immunology</i> https://doi.org/10.1038/s41590-025-02234-3, published online 12 August 2025.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"35 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002991","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}
Nature ImmunologyPub Date : 2025-09-05DOI: 10.1038/s41590-025-02277-6
Nanyang Xiao, Airi Kogishi, Lisa Radochonski, Yuchong Lei, Jueqi Chen
{"title":"Type A cholesterol-dependent cytolysins translocate to the trans-Golgi network for NLRP3 inflammasome activation","authors":"Nanyang Xiao, Airi Kogishi, Lisa Radochonski, Yuchong Lei, Jueqi Chen","doi":"10.1038/s41590-025-02277-6","DOIUrl":"10.1038/s41590-025-02277-6","url":null,"abstract":"Cholesterol-dependent cytolysins (CDCs) constitute the largest group of pore-forming toxins and serve as critical virulence factors for diverse pathogenic bacteria. Several CDCs are known to activate the NLRP3 inflammasome, although the mechanisms are unclear. Here we discovered that multiple CDCs, which we referred to as type A CDCs, were internalized and translocated to the trans-Golgi network (TGN) to remodel it into a platform for NLRP3 activation through a unique peeling membrane mechanism. Potassium efflux was dispensable for CDC-mediated TGN remodeling and NLRP3 recruitment, but was required for the recruitment of the downstream adaptor ASC. In contrast, desulfolysin, which we referred to as type B CDC, was not internalized or translocated to the TGN due to its distinct C-terminal domain 4, despite potent pore formation on the plasma membrane, and hence could not activate NLRP3. Our discoveries uncovered the ability of CDCs to directly remodel an intracellular organelle for inflammatory response. Chen and colleagues show that type A cholesterol-dependent cytolysins, a group of bacteria pore-forming toxins, translocate to the trans-Golgi network to remodel it into a platform for NLRP3 activation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 10","pages":"1673-1685"},"PeriodicalIF":27.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995783","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}
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