{"title":"Gasdermin-D-mediated epithelial-immune circuit synchronizes nutrient absorption and host defense in the small intestine","authors":"Qianzhou Yu, Danlu Jiang, Tianming Zhao, Yuelin Guan, Jian Zhang, Dehang Yang, Ruya Sun, Weiwei Yu, Zhen Wang, Sheng Chen, Mobai Li, Tianyi Hu, Qiqi Deng, Xiaoyang Lu, Yidong Yang, Mengfei Chang, Liheng Du, Xue Zhang, Zhexu Chi, Di Wang","doi":"10.1016/j.immuni.2025.06.019","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.06.019","url":null,"abstract":"The small intestine (SI) absorbs nutrients and acts as a barrier against pathogens. Diet enables the absorptive function of the SI while maintaining immune homeostasis. But how the SI transmits nutritional signals to the immune response and adapts to dietary intake remains unclear. Here, we demonstrated that epithelial gasdermin D (GSDMD) in the SI facilitated the absorptive function of enterocytes, subsequently empowering an epithelial-immune cooperation to modulate host defense. Unlike its pyroptotic function, GSDMD determines the absorptive versus the defensive zonation of enterocytes and promotes brush border assembly. This diet-induced, GSDMD-mediated adaptation promoted lipid absorption and subsequently rewired enterocyte metabolism to support intraepithelial γδ T lymphocytes (γδ T-IELs), thereby enhancing barrier function. Impairment of this GSDMD-mediated circuit exacerbated barrier-dysfunction-associated enteritis. Our results reveal how epithelial cells and lymphocytes co-adapt to nutrient signals in the SI, thereby adjusting the equilibrium between nutrient uptake and host defense in response to environmental change.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"703 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693788","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}
ImmunityPub Date : 2025-07-22DOI: 10.1016/j.immuni.2025.07.014
Korneliusz Golebski, Janice A. Layhadi, Umit Sahiner, Esther H. Steveling-Klein, Madison M. Lenormand, Rachael C.Y. Li, Suzanne M. Bal, Balthasar A. Heesters, Gemma Vilà-Nadal, Oliver Hunewald, Guillem Montamat, Feng Q. HeFeng, Markus Ollert, Oleksandra Fedina, Mongkol Lao-Araya, Susanne J.H. Vijverberg, Anke-Hilse Maitland-van der Zee, Cornelis M. van Drunen, Wytske J. Fokkens, Stephen R. Durham, Mohamed H. Shamji
{"title":"Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response","authors":"Korneliusz Golebski, Janice A. Layhadi, Umit Sahiner, Esther H. Steveling-Klein, Madison M. Lenormand, Rachael C.Y. Li, Suzanne M. Bal, Balthasar A. Heesters, Gemma Vilà-Nadal, Oliver Hunewald, Guillem Montamat, Feng Q. HeFeng, Markus Ollert, Oleksandra Fedina, Mongkol Lao-Araya, Susanne J.H. Vijverberg, Anke-Hilse Maitland-van der Zee, Cornelis M. van Drunen, Wytske J. Fokkens, Stephen R. Durham, Mohamed H. Shamji","doi":"10.1016/j.immuni.2025.07.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.07.014","url":null,"abstract":"No Abstract","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677346","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}
ImmunityPub Date : 2025-07-22DOI: 10.1016/j.immuni.2025.06.018
Surya P. Pandey, Donghui Yang, Lee Hedden, Colin R. Laughlin, Weihong Wang, Ariadna S. Soto, Halah Winner, Luzmariel Medina Sanchez, Edith E. Campana, Clarisse Engl, Yanlin Zeng, Mohit Rana, Lauren Van Der Kraak, Mackenzie J. Bender, Joshua Prokopec, Julia M. Ferrick, Xinan Meng, Erica Fong, Mai Sun, Steven J. Mullett, Reinhard Hinterleitner
{"title":"Gasdermin C cleavage by Cathepsin S modulates Rab7 vesicles in intestinal epithelial cells to amplify anti-helminth immunity","authors":"Surya P. Pandey, Donghui Yang, Lee Hedden, Colin R. Laughlin, Weihong Wang, Ariadna S. Soto, Halah Winner, Luzmariel Medina Sanchez, Edith E. Campana, Clarisse Engl, Yanlin Zeng, Mohit Rana, Lauren Van Der Kraak, Mackenzie J. Bender, Joshua Prokopec, Julia M. Ferrick, Xinan Meng, Erica Fong, Mai Sun, Steven J. Mullett, Reinhard Hinterleitner","doi":"10.1016/j.immuni.2025.06.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.06.018","url":null,"abstract":"Gasdermins are canonically associated with plasma membrane pore formation and lytic cell death. Gasdermin C (GsdmC), predominantly expressed in intestinal epithelial cells (IECs), seems to operate independently of these canonical roles. Here, we show that activated GsdmC is increased in response to type 2 immunity in the gut, driven by Cathepsin S (CTSS)-mediated cleavage. Although IEC cell death is not the main consequence of GsdmC cleavage, inserting a single amino acid (aa) within the lipid-binding motif to match that of the other gasdermins enhanced GsdmC oligomerization and increased GsdmC-mediated cell death. Mechanistically, instead of localizing to the plasma membrane, we showed that cleaved GsdmC targeted Rab7<sup>+</sup> vesicles, such as late endosomes. This modulated lipid droplet accumulation, which promoted goblet cell hyperplasia and type 2 immune responses. These findings demonstrate how GsdmC in IEC protects against helminth infection and expands the role of gasdermins beyond cell death and cytokine release.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"83 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677304","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}
ImmunityPub Date : 2025-07-17DOI: 10.1016/j.immuni.2025.06.017
Marco Di Gioia, Valentina Poli, Piao J. Tan, Roberto Spreafico, Anne Chu, Alex G. Cuenca, Zhongyang Wu, Mehdi Benamar, Laura Pandolfi, Federica Meloni, Fatemeh Askarian, Jason Hsiao, Elizaveata Borroum, Victor Nizet, Philip L.S.M. Gordts, Joseph L. Witztum, Talal A. Chatila, Janet Chou, Xu Zhou, James R. Springstead, Ivan Zanoni
{"title":"Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections","authors":"Marco Di Gioia, Valentina Poli, Piao J. Tan, Roberto Spreafico, Anne Chu, Alex G. Cuenca, Zhongyang Wu, Mehdi Benamar, Laura Pandolfi, Federica Meloni, Fatemeh Askarian, Jason Hsiao, Elizaveata Borroum, Victor Nizet, Philip L.S.M. Gordts, Joseph L. Witztum, Talal A. Chatila, Janet Chou, Xu Zhou, James R. Springstead, Ivan Zanoni","doi":"10.1016/j.immuni.2025.06.017","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.06.017","url":null,"abstract":"Phagocytes initiate immunity to invading microorganisms by detecting pathogen-associated molecular patterns via pattern recognition receptors. Pathogen encounter and consequent activation of the immune system cause tissue damage and the release of host-derived damage-associated molecular patterns, contributing to shape immunity. However, how self-derived factors are sensed by phagocytes and impact the immune response remains poorly understood. Here, we demonstrated that host-derived oxidized phospholipids (oxPLs) are formed after microbial encounter in both mice and humans. oxPLs exacerbated inflammation without affecting pathogen burden. Mechanistically, oxPLs bound and inhibited AKT, potentiating the methionine cycle and the activity of the epigenetic writer EZH2. EZH2 epigenetically dampened the pluripotent anti-inflammatory cytokine IL-10, contributing to the death of the host. Overall, we found that host-derived oxPLs set the balance between protective and detrimental antimicrobial responses and that they can be prophylactically or therapeutically targeted to protect the host against deranged inflammation and immunopathology.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"3 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645794","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}
ImmunityPub Date : 2025-07-16DOI: 10.1016/j.immuni.2025.06.011
Tao Deng, Xi Jiang, Zihan Zhao, Xinlu Zhao, Angzhi Bi, Shian Ouyang, Shiming Sun, Shuang Qiu, Mingxin Fan, Qi Xue, Wenhao Yu, Yang Yang, Wannan Li, Yunze Wu, Xinrui Huang, Da Zhong, Shan Qin, Wenqi Zhu, Jie P. Li
{"title":"CINTER-seq: Chemical profiling reveals interaction-dependent cell landscapes and gene signatures in vivo","authors":"Tao Deng, Xi Jiang, Zihan Zhao, Xinlu Zhao, Angzhi Bi, Shian Ouyang, Shiming Sun, Shuang Qiu, Mingxin Fan, Qi Xue, Wenhao Yu, Yang Yang, Wannan Li, Yunze Wu, Xinrui Huang, Da Zhong, Shan Qin, Wenqi Zhu, Jie P. Li","doi":"10.1016/j.immuni.2025.06.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.06.011","url":null,"abstract":"Physical interactions between cells are essential for physiological functions, yet the <em>in situ</em> cellular interactome remains largely unexplored. In this study, we developed a photocatalytic chemistry to capture targeted physically interacting cells in living mice. Furthermore, we introduce sequencing of the cellular interactome (CINTER-seq), a quantitative approach for multiplexed indexing of the captured cellular interactome, enabled by the simultaneous <em>ex situ</em> sequencing of multidimensional parameters. Using this system, we have revealed interaction-dependent gene signatures of immune cells <em>in vivo</em>, providing molecular insights into their interactions. Notably, we find that the immune checkpoint lymphocyte-activation gene 3 (LAG3) can mediate stable T cell-antigen-presenting cell (APC) contacts only by interacting with major histocompatibility complex class II (MHC class II) molecules, while neutrophils are strongly activated through interactions with tumor cells to adopt a pro-tumor phenotype in an interaction-dependent manner. These results underscore the potential of the CINTER-seq platform to make <em>in vivo</em> cellular interactome decoding routines in future studies.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"2 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640495","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}
ImmunityPub Date : 2025-07-15DOI: 10.1016/j.immuni.2025.06.016
Yan Wang, Di Xu, Shaorui Liu, Haoyang Li, Yinsheng Wang, Hui Li, Heping Xu, Danyang He
{"title":"Cognate interaction-dependent pathogenicity of meningeal B cells drives neuroinflammation relapse","authors":"Yan Wang, Di Xu, Shaorui Liu, Haoyang Li, Yinsheng Wang, Hui Li, Heping Xu, Danyang He","doi":"10.1016/j.immuni.2025.06.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.06.016","url":null,"abstract":"B cells are central drivers of central nervous system (CNS) autoimmune disorders, including multiple sclerosis (MS). Although the brain meninges normally maintain a stringently non-self-reactive B cell repertoire, how disruption of this local immune tolerance contributes to pathology remains unclear. Here, we demonstrated that autoreactive B cells at the brain border accelerated neuroinflammation by directly engaging encephalitogenic T cells. Intracisterna magna injections, used to selectively manipulate meningeal B cell populations in the 2D2 transfer experimental autoimmune encephalomyelitis (EAE) model, revealed that autoreactive B-T interactions in the leptomeninges amplified a local pro-inflammatory loop, promoting neutrophil recruitment and endothelial activation before disease onset. This mechanism required major histocompatibility complex class II (MHC class II) expression by B cells and granulocyte-macrophage colony-stimulating factor (GM-CSF) production by T cells. Furthermore, targeted depletion of brain-localized B cells attenuated EAE relapses in a passive EAE model. These findings establish brain-localized autoreactive B cells as crucial initiators of neuroinflammation and promising therapeutic targets in relapsing MS.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"10 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629957","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}
ImmunityPub Date : 2025-07-14DOI: 10.1016/j.immuni.2025.06.014
Maximilian Julius Lautenbach, Katja Wyss, Victor Yman, Fariba Foroogh, Donya Satarvandi, Zaynab Mousavian, Klara Sondén, Jun Wang, María Bueno Álvez, Sofia Bergström, Peter Nilsson, Fredrik Edfors, Petter Brodin, Mathias Uhlén, Christopher Sundling, Anna Färnert
{"title":"Systems analysis of clinical malaria reveals proteomic perturbation and innate-adaptive crosstalk linked to disease severity","authors":"Maximilian Julius Lautenbach, Katja Wyss, Victor Yman, Fariba Foroogh, Donya Satarvandi, Zaynab Mousavian, Klara Sondén, Jun Wang, María Bueno Álvez, Sofia Bergström, Peter Nilsson, Fredrik Edfors, Petter Brodin, Mathias Uhlén, Christopher Sundling, Anna Färnert","doi":"10.1016/j.immuni.2025.06.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.06.014","url":null,"abstract":"Malaria presents with varying degrees of severity. To improve clinical management and prevention, it is crucial to understand the pathogenesis and host response. We analyzed 1,463 plasma proteins during and after acute <em>Plasmodium falciparum</em> malaria in adult travelers and linked responses to peripheral immune cells by integrating with single-cell RNA sequencing (RNA-seq) data from a subset of donors. We identified extensive perturbations in over 250 proteins with diverse origins, including many not previously analyzed in malaria patients, such as hormones, circulating receptors, and intracellular or membrane-bound proteins from affected tissues. The protein profiles clustered participants according to disease severity, enabling the identification of a compressed 11-protein signature enriched in severe malaria. Conceptually, this study advances our understanding of malaria by linking systemic proteomic changes to immune cell communication and organ-specific responses. This resource, which includes an interactive platform to explore data, opens new avenues for hypothesis generation, biomarker discovery, and therapeutic target identification.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"4 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622369","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}
ImmunityPub Date : 2025-07-08DOI: 10.1016/j.immuni.2025.06.008
Máté Kiss, Mikael J. Pittet
{"title":"Mitochondrial control of macrophage polarity in tumors","authors":"Máté Kiss, Mikael J. Pittet","doi":"10.1016/j.immuni.2025.06.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.06.008","url":null,"abstract":"Macrophages can foster pro- or anti-tumor immune environments. In this issue of <em>Immunity</em>, Clark et al. report that altering the composition of the mitochondrial electron transport chain reprograms macrophages toward a CXCL9<sup>hi</sup>SPP1<sup>lo</sup> immunostimulatory phenotype, thus amplifying anti-tumor immunity.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"196 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578498","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}
ImmunityPub Date : 2025-07-08DOI: 10.1016/j.immuni.2025.06.009
José Pedro Loureiro, Gennaro De Libero
{"title":"The Three Graces of T cell receptor Vγ9Vδ2 chain activation","authors":"José Pedro Loureiro, Gennaro De Libero","doi":"10.1016/j.immuni.2025.06.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.06.009","url":null,"abstract":"T cells expressing the T cell receptor (TCR) Vγ9Vδ2 chains recognize butyrophilins (BTNs) in the presence of phosphorylated antigens (pAgs). In this issue of <em>Immunity</em>, Zhang et al. and Zhu et al. illustrate the mechanism of TCR-BTN interaction using cryo-electron microscopy (cryo-EM). As pAgs accumulate, BTN heterotetramers assemble to bind to and activate the TCR Vγ9Vδ2.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"109 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578078","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}
ImmunityPub Date : 2025-07-08DOI: 10.1016/j.immuni.2025.06.012
Brian L. Kelsall
{"title":"RORγt+ dendritic cells and regulatory T cells: A couple hiding in the shadows","authors":"Brian L. Kelsall","doi":"10.1016/j.immuni.2025.06.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.06.012","url":null,"abstract":"The induction of CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (pTreg cells) in the intestine is important for preventing allergic and inflammatory disease, but which cells drive their differentiation is less clear. Three manuscripts in <em>Nature</em>, <em>Cell</em>, and <em>Science</em> conclude that one population of RORγt<sup>+</sup> “dendritic cells” (DCs) is essential for both food- and microbe-specific pTreg cell responses in the intestine.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"21 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578337","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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