{"title":"Luck gone cold: A trifecta of B cell mutations associates with cryoglobulinemia","authors":"Kangzhi Chen, Kevin C. O’Connor","doi":"10.1126/sciimmunol.adx6827","DOIUrl":"10.1126/sciimmunol.adx6827","url":null,"abstract":"<div >Triple somatic mutations in autoreactive B cells contribute to virus-associated autoimmune disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 106","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784344","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}
Daniel A. Waizman, Isabela Brown-Soler, Anjelica L. Martin, Yifan Ma, Kenneth Zhou, Kavita Israni-Winger, Cuiling Zhang, Ruslan Medzhitov, Pierre Launay, Michaël F. Michieletto, Jorge Henao-Mejia, Noah W. Palm, Joe Craft, Anna Eisenstein, Andrew Wang
{"title":"Skin damage signals mediate allergic sensitization to spatially unlinked antigen","authors":"Daniel A. Waizman, Isabela Brown-Soler, Anjelica L. Martin, Yifan Ma, Kenneth Zhou, Kavita Israni-Winger, Cuiling Zhang, Ruslan Medzhitov, Pierre Launay, Michaël F. Michieletto, Jorge Henao-Mejia, Noah W. Palm, Joe Craft, Anna Eisenstein, Andrew Wang","doi":"10.1126/sciimmunol.adn0688","DOIUrl":"10.1126/sciimmunol.adn0688","url":null,"abstract":"<div >Our current understanding of immunity to pathogens suggests that anatomic coupling of antigens with danger signals is a required feature for the formation of immune memory. However, in the context of pathogen-independent inflammation, the stringency of this anatomical coupling is unclear. Here, we demonstrate that multiple modes of skin injury were sufficient to induce a humoral response to antigens introduced in the gut. Skin damage induced a narrow subset of endocrine cytokines that were necessary and sufficient for the priming of antigens introduced at various distal tissues. Thus, in addition to “local priming” of antigen entering through damaged skin, there also exists another paradigm of “remote priming” where anatomical coupling is not essential because of the dissemination of damage-associated intermediaries. Our findings have implications for understanding the fundamental mechanisms of the formation of humoral memory with wide implications for diseases such as food allergy and in vaccinology.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 106","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782476","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}
Joao Paulo Cavalcanti de Albuquerque, Jenna Hunter, Rita G. Domingues, Erika Harno, Amy A. Worth, Fabrizio Maria Liguori, Aurora D’Alessio, Gabriella Aviello, David Bechtold, Anne White, Simon M. Luckman, Matthew R. Hepworth, Giuseppe D’Agostino
{"title":"Brain sensing of metabolic state regulates circulating monocytes","authors":"Joao Paulo Cavalcanti de Albuquerque, Jenna Hunter, Rita G. Domingues, Erika Harno, Amy A. Worth, Fabrizio Maria Liguori, Aurora D’Alessio, Gabriella Aviello, David Bechtold, Anne White, Simon M. Luckman, Matthew R. Hepworth, Giuseppe D’Agostino","doi":"10.1126/sciimmunol.adr3226","DOIUrl":"10.1126/sciimmunol.adr3226","url":null,"abstract":"<div >Changes in energy availability alter the dynamics of circulating immune cells. The existing view is that these effects are due to altered nutrient levels affecting peripheral tissue metabolism. Here, using mice and genetic approaches to manipulate the activity of distinct molecularly defined neurons, we show that the brain’s perception of hunger and satiety alone is sufficient to drive these immune changes. Hunger-promoting Agouti-related peptide (AgRP) neurons in the hypothalamus were both sufficient and necessary to reduce circulating Ly6C<sup>Hi</sup> classical monocytes during fasting. Mechanistically, these neurons suppressed hepatic mammalian target of rapamycin signaling via sympathetic regulation, decreasing circulating chemokine ligand 2 and monocyte numbers. AgRP neuron–induced corticosterone release and glucocorticoid receptor activation played a permissive role in this process. These changes in monocyte dynamics can occur independently of actual nutrient levels, revealing an unexpected brain-mediated control of peripheral immunity in response to perceived variation in energy state.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 106","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adr3226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782478","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}
Mariem Radhouani, Asma Farhat, Anna Hakobyan, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anastasiya Hladik, Karin Lakovits, Jessica Brösamlen, Vojtech Dvorak, Natalia Nunes, Andreas Zech, Marco Idzko, Thomas Krausgruber, Jörg Köhl, Ozge Uluckan, Jiri Kovarik, Kai Hoehlig, Axel Vater, Margret Eckhard, Andy Sombke, Nikolaus Fortelny, Jörg Menche, Sylvia Knapp, Philipp Starkl
{"title":"Eosinophil innate immune memory after bacterial skin infection promotes allergic lung inflammation","authors":"Mariem Radhouani, Asma Farhat, Anna Hakobyan, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anastasiya Hladik, Karin Lakovits, Jessica Brösamlen, Vojtech Dvorak, Natalia Nunes, Andreas Zech, Marco Idzko, Thomas Krausgruber, Jörg Köhl, Ozge Uluckan, Jiri Kovarik, Kai Hoehlig, Axel Vater, Margret Eckhard, Andy Sombke, Nikolaus Fortelny, Jörg Menche, Sylvia Knapp, Philipp Starkl","doi":"10.1126/sciimmunol.adp6231","DOIUrl":"10.1126/sciimmunol.adp6231","url":null,"abstract":"<div >Microbial exposure at barrier interfaces drives development and balance of the immune system, but the consequences of local infections for systemic immunity and secondary inflammation are unclear. Here, we show that skin exposure to the bacterium <i>Staphylococcus aureus</i> persistently shapes the immune system of mice with specific impact on progenitor and mature bone marrow neutrophil and eosinophil populations. The infection-imposed changes in eosinophils were long-lasting and associated with functional as well as imprinted epigenetic and metabolic changes. Bacterial exposure enhanced cutaneous allergic sensitization and resulted in exacerbated allergen-induced lung inflammation. Functional bone marrow eosinophil reprogramming and pulmonary allergen responses were driven by the alarmin interleukin-33 and the complement cleavage fragment C5a. Our study highlights the systemic impact of skin inflammation and reveals mechanisms of eosinophil innate immune memory and organ cross-talk that modulate systemic responses to allergens.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 106","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782477","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":"They are what they eat","authors":"Asha Pillai","doi":"10.1126/sciimmunol.adx7179","DOIUrl":"10.1126/sciimmunol.adx7179","url":null,"abstract":"<div >The viability of ingested bacterial pathogens can alter the metabolic program and cytokine secretion of macrophages.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 106","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784339","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":"Immunogenomic cancer evolution: A framework to understand cancer immunosuppression","authors":"Shogo Kumagai, Yusaku Momoi, Hiroyoshi Nishikawa","doi":"10.1126/sciimmunol.abo5570","DOIUrl":"10.1126/sciimmunol.abo5570","url":null,"abstract":"<div >The process of tumor development involves tumor cells eluding detection and suppression of immune responses, which can cause decreased tumor cell antigenicity, expression of immunosuppressive molecules, and immunosuppressive cell recruitment to the tumor microenvironment (TME). Immunologically and genomically integrated analysis (immunogenomic analysis) of patient specimens has revealed that oncogenic aberrant signaling is involved in both carcinogenesis and immune evasion. In noninflamed cancers such as <i>epidermal growth factor receptor</i> (<i>EGFR</i>)–mutated lung cancers, genetic abnormalities in cancer cells contribute to the formation of an immunosuppressive TME by recruiting immunosuppressive cells, which cannot be fully explained by the cancer immunoediting hypothesis. This review summarizes the latest findings regarding the links between cancer genetic abnormalities and immunosuppression causing clinical resistance to immunotherapy. We propose the concepts of immunogenomic cancer evolution, in which cancer cell genomic evolution shapes the immunosuppressive TME, and immunogenomic precision medicine, in which cancer immunotherapy can be combined with molecularly targeted reagents that modulate the immunosuppressive TME.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723818","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}
Asma Farhat, Mariem Radhouani, Florian Deckert, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anna Hakobyan, Felicitas Oberndorfer, Jessica Brösamlen, Anastasiya Hladik, Karin Lakovits, Fanzhe Meng, Federica Quattrone, Louis Boon, Cornelia Vesely, Philipp Starkl, Nicole Boucheron, Jörg Menche, Joris van der Veeken, Wilfried Ellmeier, Anna-Dorothea Gorki, Clarissa Campbell, Riem Gawish, Sylvia Knapp
{"title":"An aging bone marrow exacerbates lung fibrosis by fueling profibrotic macrophage persistence","authors":"Asma Farhat, Mariem Radhouani, Florian Deckert, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anna Hakobyan, Felicitas Oberndorfer, Jessica Brösamlen, Anastasiya Hladik, Karin Lakovits, Fanzhe Meng, Federica Quattrone, Louis Boon, Cornelia Vesely, Philipp Starkl, Nicole Boucheron, Jörg Menche, Joris van der Veeken, Wilfried Ellmeier, Anna-Dorothea Gorki, Clarissa Campbell, Riem Gawish, Sylvia Knapp","doi":"10.1126/sciimmunol.adk5041","DOIUrl":"10.1126/sciimmunol.adk5041","url":null,"abstract":"<div >Pulmonary fibrosis is an incurable disease that manifests with advanced age. Yet, how hematopoietic aging influences immune responses and fibrosis progression remains unclear. Using heterochronic bone marrow transplant mouse models, we found that an aged bone marrow exacerbates lung fibrosis irrespective of lung tissue age. Upon lung injury, there was an increased accumulation of monocyte-derived alveolar macrophages (Mo-AMs) driven by cell-intrinsic hematopoietic aging. These Mo-AMs exhibited an enhanced profibrotic profile and stalled maturation into a homeostatic, tissue-resident phenotype. This delay was shaped by cell-extrinsic environmental signals such as reduced pulmonary interleukin-10 (IL-10), perpetuating a profibrotic macrophage state. We identified regulatory T cells (T<sub>regs</sub>) as critical providers of IL-10 upon lung injury that promote Mo-AM maturation and attenuate fibrosis progression. Our study highlights the impact of an aging bone marrow on lung immune regulation and identifies T<sub>reg</sub>-mediated IL-10 signaling as a promising target to mitigate fibrosis and promote tissue repair.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adk5041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723816","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}
Kathleen A. M. Mills, Frederike Westermann, Vanessa Espinosa, Eric Rosiek, Jigar V. Desai, Mariano A. Aufiero, Yahui Guo, Fitty L. Liu, Kennedy A. Mitchell, Selma Tuzlak, Donatella De Feo, Michail S. Lionakis, Amariliz Rivera, Burkhard Becher, Tobias M. Hohl
{"title":"GM-CSF–mediated epithelial-immune cell cross-talk orchestrates pulmonary immunity to Aspergillus fumigatus","authors":"Kathleen A. M. Mills, Frederike Westermann, Vanessa Espinosa, Eric Rosiek, Jigar V. Desai, Mariano A. Aufiero, Yahui Guo, Fitty L. Liu, Kennedy A. Mitchell, Selma Tuzlak, Donatella De Feo, Michail S. Lionakis, Amariliz Rivera, Burkhard Becher, Tobias M. Hohl","doi":"10.1126/sciimmunol.adr0547","DOIUrl":"10.1126/sciimmunol.adr0547","url":null,"abstract":"<div ><i>Aspergillus fumigatus</i> causes life-threatening mold pneumonia in immunocompromised patients, particularly in those with quantitative or qualitative defects in neutrophils. Whereas innate immune cell cross-talk licenses neutrophil antifungal activity in the lung, the role of epithelial cells in this process is unknown. Here, we find that surfactant protein C (SPC)–expressing lung epithelial cells integrate infection-induced interleukin-1 and type III interferon signaling to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) preferentially at local sites of fungal infection and neutrophil influx. Using in vivo models that distinguish the role of GM-CSF during acute infection from its homeostatic function in alveolar macrophage survival and surfactant catabolism, we demonstrate that epithelial-derived GM-CSF increases the accumulation and fungicidal activity of GM-CSF–responsive neutrophils, which is essential for host survival. Our findings establish SPC<sup>+</sup> epithelial cells as a central player in regulating the quality and strength of neutrophil-dependent immunity against inhaled mold pathogens.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adr0547","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666292","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}
Yao Li, Jiongliang Wang, Linfu Zhou, Wenbin Gu, Le Qin, Dongdong Peng, Shanglin Li, Diwei Zheng, Qiting Wu, Youguo Long, Yao Yao, Shouheng Lin, Mingwei Sun, Xiaofei Zhang, Jie Wang, Pentao Liu, Xiangqian Kong, Peng Li
{"title":"DNMT1 inhibition reprograms T cells to NK-like cells with potent antitumor activity","authors":"Yao Li, Jiongliang Wang, Linfu Zhou, Wenbin Gu, Le Qin, Dongdong Peng, Shanglin Li, Diwei Zheng, Qiting Wu, Youguo Long, Yao Yao, Shouheng Lin, Mingwei Sun, Xiaofei Zhang, Jie Wang, Pentao Liu, Xiangqian Kong, Peng Li","doi":"10.1126/sciimmunol.adm8251","DOIUrl":"10.1126/sciimmunol.adm8251","url":null,"abstract":"<div >Inactivation of the transcription factor BCL11B reprograms T cells into induced-T-to-NK cells (ITNKs). However, it remains unclear how BCL11B suppresses natural killer (NK) cell transcriptional programs. Here, we identified that the DNA methyltransferase DNMT1 physically interacts with BCL11B, increasing BCL11B stability and the fidelity of DNA methylation maintenance for NK cell–related genes, thereby repressing their expression. Moreover, DNMT1 maintains the epigenetic silencing of a distinct subset of NK cell–related genes independent of BCL11B. DNMT1 inhibition or depletion reprograms T cells and chimeric antigen receptor (CAR)–T cells into NK-like cells that exhibit more robust antitumor effects than BCL11B-deficient ITNKs and parental CAR-T cells. Moreover, H3K27me3 (trimethylation of histone 3 lysine 27) synergizes with DNA methylation to repress NK cell–related pathways, and combined EZH2 (enhancer of zeste homolog 2) and DNMT1 inhibition potentiates both the reprogramming and cytotoxicity of NK-like cells. Our findings uncover the molecular mechanisms that safeguard T cell identity and provide a rationale for deriving NK-like cells with epigenetic inhibitors for cancer immunotherapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665976","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}
Weili Xu, Natasha B. Golovchenko, Irving U. Martínez-Vargas, Andrew Fong, Prateeksha Rout, Sajan Achi, Edie B. Bucar, Jonathan J. Hsieh, Kaylynn J. Vidmar, Lanjing Zhang, Alexandros D. Polydorides, Immo Prinz, George Kollias, Mark R. Frey, Theresa T. Pizarro, Michael P. Verzi, Karen L. Edelblum
{"title":"Dysregulation of γδ intraepithelial lymphocytes precedes Crohn’s disease–like ileitis","authors":"Weili Xu, Natasha B. Golovchenko, Irving U. Martínez-Vargas, Andrew Fong, Prateeksha Rout, Sajan Achi, Edie B. Bucar, Jonathan J. Hsieh, Kaylynn J. Vidmar, Lanjing Zhang, Alexandros D. Polydorides, Immo Prinz, George Kollias, Mark R. Frey, Theresa T. Pizarro, Michael P. Verzi, Karen L. Edelblum","doi":"10.1126/sciimmunol.adk7429","DOIUrl":"10.1126/sciimmunol.adk7429","url":null,"abstract":"<div >Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) provide immunosurveillance of the intestinal barrier but are reduced in patients with active Crohn’s disease (CD). Here, we report an underappreciated role for γδ IELs in maintaining immunological tolerance during the onset and progression of CD-like ileitis using TNF<sup>ΔARE/+</sup> mice. We found that TNF-induced down-regulation of epithelial hepatocyte nuclear factor 4-gamma/butyrophilin is followed by a loss of ileal Vγ7 IELs and impaired barrier surveillance before the histological onset of disease. A reduction of immunoregulatory CD39<sup>+</sup> γδ IELs coincided with the influx of immature, peripheral CD39<sup>neg</sup> γδ T cells into the epithelium, leading to an expansion of induced IELs, whereas an earlier depletion of γδ IELs correlated with accelerated onset of ileal inflammation. Our findings identify multiple layers of γδ IEL dysregulation before ileitis development, indicating that the loss of steady-state immunoregulatory γδ IELs may contribute to the initiation of ileal CD.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666294","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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