Nature ImmunologyPub Date : 2025-04-30DOI: 10.1038/s41590-025-02144-4
Chunxing Zheng, Shaofeng Liu, Nastaran Fazel Modares, Michael St. Paul, Tak W. Mak
{"title":"Cholinergic T cells revitalize the tumor immune microenvironment: TIME to ChAT","authors":"Chunxing Zheng, Shaofeng Liu, Nastaran Fazel Modares, Michael St. Paul, Tak W. Mak","doi":"10.1038/s41590-025-02144-4","DOIUrl":"https://doi.org/10.1038/s41590-025-02144-4","url":null,"abstract":"<p>Crosstalk between the nervous system and the immune system shapes the tumor microenvironment. Cholinergic T cells, a unique population of T cell antigen receptor-induced acetylcholine-producing T cells, have emerged as an integrative interface between these two fundamental body systems. Here we review the distinct characteristics and functions of cholinergic T cells in cancer settings. We first outline the expression of choline acetyltransferase and the cholinergic machinery in T cells. We then describe the dysfunctional state of choline acetyltransferase-expressing T cells in cancer and delve into their modulatory effects on T cells, cancer cells and the tumor microenvironment, including its populations of immune cells, its vasculature and its nerves. We also discuss the clinical implications of harnessing the potential of cholinergic T cells and future directions for increasing our understanding of their importance and possible exploitation.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"37 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893201","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 : 2025-04-29DOI: 10.1038/s41590-025-02148-0
{"title":"Acetylcholine-secreting B cells constrain macrophage responses to influenza virus","authors":"","doi":"10.1038/s41590-025-02148-0","DOIUrl":"https://doi.org/10.1038/s41590-025-02148-0","url":null,"abstract":"In our study, we identify a regulatory pathway by which release of the neurotransmitter acetylcholine by B cells suppresses TNF production by lung interstitial macrophages early in influenza virus infection. In this way, B cells reduce early lung inflammation and support eventual tissue regeneration, despite reducing early control of viral replication.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"35 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884826","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 : 2025-04-23DOI: 10.1038/s41590-025-02143-5
{"title":"Interferon-β treatment restores myeloid function and reverses immunosuppression in sepsis","authors":"","doi":"10.1038/s41590-025-02143-5","DOIUrl":"https://doi.org/10.1038/s41590-025-02143-5","url":null,"abstract":"Systemic inflammation, such as sepsis, starts with excessive inflammation and is followed by a long-lasting immunosuppressed state. Using single-cell transcriptomics and functional assays, we show that the immunosuppression is driven by impaired monocyte maturation and reduced type I interferon signaling, which could be reversed by treatment with interferon-β.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"32 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862801","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 : 2025-04-22DOI: 10.1038/s41590-025-02124-8
Antonio Cembellin-Prieto, Zheng Luo, Heather Kulaga, Nicole Baumgarth
{"title":"B cells modulate lung antiviral inflammatory responses via the neurotransmitter acetylcholine","authors":"Antonio Cembellin-Prieto, Zheng Luo, Heather Kulaga, Nicole Baumgarth","doi":"10.1038/s41590-025-02124-8","DOIUrl":"https://doi.org/10.1038/s41590-025-02124-8","url":null,"abstract":"<p>The rapid onset of innate immune defenses is critical for early control of viral replication in an infected host and yet it can also lead to irreversible tissue damage, especially in the respiratory tract. Sensitive regulators must exist that modulate inflammation, while controlling the infection. In the present study, we identified acetylcholine (ACh)-producing B cells as such early regulators. B cells are the most prevalent ACh-producing leukocyte population in the respiratory tract demonstrated with choline acetyltransferase (ChAT)-green fluorescent protein (GFP) reporter mice, both before and after infection with influenza A virus. Mice lacking ChAT in B cells, disabling their ability to generate ACh (ChatBKO), but not those lacking ChAT in T cells, significantly, selectively and directly suppressed α7-nicotinic-ACh receptor-expressing interstitial, but not alveolar, macrophage activation and their ability to secrete tumor necrosis factor (TNF), while better controlling virus replication at 1 d postinfection. Conversely, TNF blockade via monoclonal antibody treatment increased viral loads at that time. By day 10 of infection, ChatBKO mice showed increased local and systemic inflammation and reduced signs of lung epithelial repair despite similar viral loads and viral clearance. Thus, B cells are key participants of an immediate early regulatory cascade that controls lung tissue damage after viral infection, shifting the balance toward reduced inflammation at the cost of enhanced early viral replication.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"6 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857505","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 : 2025-04-22DOI: 10.1038/s41590-025-02132-8
Danya Thayaparan, Takuo Emoto, Aniqa B. Khan, Rickvinder Besla, Homaira Hamidzada, Mahmoud El-Maklizi, Tharini Sivasubramaniyam, Shabana Vohra, Ash Hagerman, Sara Nejat, Charlotte E. Needham-Robbins, Tao Wang, Moritz Lindquist, Steven R. Botts, Stephanie A. Schroer, Masayuki Taniguchi, Taishi Inoue, Katsuhiro Yamanaka, Haotian Cui, Edouard Al-Chami, Hangjun Zhang, Marwan G. Althagafi, Aja Michalski, Joshua J. C. McGrath, Steven P. Cass, David Luong, Yuya Suzuki, Angela Li, Amina Abow, Rachel Heo, Shaun Pacheco, Emily Chen, Felix Chiu, John Byrne, Tomoyuki Furuyashiki, Mansoor Husain, Peter Libby, Kenji Okada, Kathryn L. Howe, Scott P. Heximer, Tomoya Yamashita, Bo Wang, Barry B. Rubin, Myron I. Cybulsky, Joy Roy, Jesse W. Williams, Sarah Q. Crome, Slava Epelman, Ken-ichi Hirata, Martin R. Stampfli, Clinton S. Robbins
{"title":"Endothelial dysfunction drives atherosclerotic plaque macrophage-dependent abdominal aortic aneurysm formation","authors":"Danya Thayaparan, Takuo Emoto, Aniqa B. Khan, Rickvinder Besla, Homaira Hamidzada, Mahmoud El-Maklizi, Tharini Sivasubramaniyam, Shabana Vohra, Ash Hagerman, Sara Nejat, Charlotte E. Needham-Robbins, Tao Wang, Moritz Lindquist, Steven R. Botts, Stephanie A. Schroer, Masayuki Taniguchi, Taishi Inoue, Katsuhiro Yamanaka, Haotian Cui, Edouard Al-Chami, Hangjun Zhang, Marwan G. Althagafi, Aja Michalski, Joshua J. C. McGrath, Steven P. Cass, David Luong, Yuya Suzuki, Angela Li, Amina Abow, Rachel Heo, Shaun Pacheco, Emily Chen, Felix Chiu, John Byrne, Tomoyuki Furuyashiki, Mansoor Husain, Peter Libby, Kenji Okada, Kathryn L. Howe, Scott P. Heximer, Tomoya Yamashita, Bo Wang, Barry B. Rubin, Myron I. Cybulsky, Joy Roy, Jesse W. Williams, Sarah Q. Crome, Slava Epelman, Ken-ichi Hirata, Martin R. Stampfli, Clinton S. Robbins","doi":"10.1038/s41590-025-02132-8","DOIUrl":"https://doi.org/10.1038/s41590-025-02132-8","url":null,"abstract":"<p>Currently there is no effective pharmacotherapy to prevent the growth and rupture of abdominal aortic aneurysms. Using a mouse model that combines cigarette smoke exposure and hypercholesterolemia, we demonstrated that cigarette smoke exacerbated atherosclerosis, leading to elastin fragmentation, aneurysm formation, rupture and death. Arterial injury was driven by macrophages that accumulated within atherosclerotic plaques and exhibited tissue-degrading proteolytic activity in vivo (a process dependent on the endothelial cell-derived macrophage growth factor CSF-1). Single-nucleus RNA sequencing revealed that cigarette smoke-induced endothelial cell dysfunction promoted monocyte recruitment and inflammatory signaling and amplified vascular injury. Furthermore, single-cell transcriptomic analysis identified conserved macrophage responses across mouse and human abdominal aortic aneurysm, including TREM2<sup>+</sup> macrophages, which were key mediators of arterial damage. These findings established atherosclerotic plaque macrophages as critical drivers of aneurysm pathology and provide key insights into the mechanisms underlying aneurysm progression and rupture.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"54 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857508","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 : 2025-04-22DOI: 10.1038/s41590-025-02134-6
Mojdeh Shakiba, David A. Tuveson
{"title":"Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer","authors":"Mojdeh Shakiba, David A. Tuveson","doi":"10.1038/s41590-025-02134-6","DOIUrl":"https://doi.org/10.1038/s41590-025-02134-6","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers that has yet to benefit from immunotherapies. This is primarily a result of its characteristic ‘cold’ tumor microenvironment composed of cancer-associated fibroblasts (CAFs), a dense network of extracellular matrix and several immune cell types, the most abundant of which are the tumor-associated macrophages (TAMs). Advances in single-cell and spatial technologies have elucidated the vast functional heterogeneity of CAFs and TAMs, their symbiotic relationship and their cooperative role in the tumor microenvironment. In this Review, we provide an overview of the heterogeneity of CAFs and TAMs, how they establish an immunosuppressive microenvironment and their collaboration in the remodeling of the extracellular matrix. Finally, we examine why the impact of immunotherapy in PDAC has been limited and how a detailed molecular and spatial understanding of the combined role of CAFs and TAMs is paramount to the design of effective therapies.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"41 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857507","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 : 2025-04-18DOI: 10.1038/s41590-025-02136-4
Farid Keramati, Guus P. Leijte, Niklas Bruse, Inge Grondman, Ehsan Habibi, Cristian Ruiz-Moreno, Wout Megchelenbrink, Annemieke M. Peters van Ton, Hidde Heesakkers, Manita E. Bremmers, Erinke van Grinsven, Kiki Tesselaar, Selma van Staveren, Walter J. van der Velden, Frank W. Preijers, Brigit te Pas, Raoul van de Loop, Jelle Gerretsen, Mihai G. Netea, Hendrik G. Stunnenberg, Peter Pickkers, Matthijs Kox
{"title":"Systemic inflammation impairs myelopoiesis and interferon type I responses in humans","authors":"Farid Keramati, Guus P. Leijte, Niklas Bruse, Inge Grondman, Ehsan Habibi, Cristian Ruiz-Moreno, Wout Megchelenbrink, Annemieke M. Peters van Ton, Hidde Heesakkers, Manita E. Bremmers, Erinke van Grinsven, Kiki Tesselaar, Selma van Staveren, Walter J. van der Velden, Frank W. Preijers, Brigit te Pas, Raoul van de Loop, Jelle Gerretsen, Mihai G. Netea, Hendrik G. Stunnenberg, Peter Pickkers, Matthijs Kox","doi":"10.1038/s41590-025-02136-4","DOIUrl":"https://doi.org/10.1038/s41590-025-02136-4","url":null,"abstract":"<p>Systemic inflammatory conditions are classically characterized by an acute hyperinflammatory phase, followed by a late immunosuppressive phase that elevates the susceptibility to secondary infections. Comprehensive mechanistic understanding of these phases is largely lacking. To address this gap, we leveraged a controlled, human in vivo model of lipopolysaccharide (LPS)-induced systemic inflammation encompassing both phases. Single-cell RNA sequencing during the acute hyperinflammatory phase identified an inflammatory <i>CD163</i><sup>+</sup><i>SLC39A8</i><sup>+</sup><i>CALR</i><sup>+</sup> monocyte-like subset (infMono) at 4 h post-LPS administration. The late immunosuppressive phase was characterized by diminished expression of type I interferon (IFN)-responsive genes in monocytes, impaired myelopoiesis and a pronounced attenuation of the immune response on a secondary LPS challenge 1 week after the first. The infMono gene program and impaired myelopoiesis were also detected in patient cohorts with bacterial sepsis and coronavirus disease. IFNβ treatment restored type-I IFN responses and proinflammatory cytokine production and induced monocyte maturation, suggesting a potential treatment option for immunosuppression.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"8 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846445","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 : 2025-04-18DOI: 10.1038/s41590-025-02133-7
{"title":"Neutrophil senescence drives sexual dimorphism in bladder cancer","authors":"","doi":"10.1038/s41590-025-02133-7","DOIUrl":"https://doi.org/10.1038/s41590-025-02133-7","url":null,"abstract":"We identify an age-related subpopulation of RETNLγ+LCN2+ senescence-like neutrophils (RLSNs) that preferentially accumulate in the tumor microenvironment of male mice and humans. RLSNs exert strong immunosuppressive functions and limit antitumor immunity, and may represent a mechanism to explain sexual dimorphism in bladder cancer.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"108 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846444","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 : 2025-04-11DOI: 10.1038/s41590-025-02126-6
Qingchen Zhu, Guiheng Zhang, Ming Cao, Huan Huang, Dan He, Zhongsheng Zang, Jing Xing, Ming Zhan, Siyu Pei, Xiuyu Deng, Juan Li, Guangxun Meng, Jing Xu, Dongfang Dai, Guohong Hu, Mingyue Zheng, Chenli Liu, Jun Qin, Yichuan Xiao
{"title":"Microbiota-shaped neutrophil senescence regulates sexual dimorphism in bladder cancer","authors":"Qingchen Zhu, Guiheng Zhang, Ming Cao, Huan Huang, Dan He, Zhongsheng Zang, Jing Xing, Ming Zhan, Siyu Pei, Xiuyu Deng, Juan Li, Guangxun Meng, Jing Xu, Dongfang Dai, Guohong Hu, Mingyue Zheng, Chenli Liu, Jun Qin, Yichuan Xiao","doi":"10.1038/s41590-025-02126-6","DOIUrl":"https://doi.org/10.1038/s41590-025-02126-6","url":null,"abstract":"<p>Sex disparities have been epidemiologically demonstrated in non-reproductive cancers, yet how the sex-specific intrinsic microbiome orchestrates the immune system to affect these disparities is unclear. Here we identify a subpopulation of RETNLG<sup>+</sup>LCN2<sup>+</sup> senescence-like neutrophils (RLSNs) that preferentially accumulate in the male tumor microenvironment and exert a strong immunosuppressive effect to limit antitumor immunity, resulting in poor prognosis for patients with bladder cancer. This difference in enrichment of RLSNs between sexes can be attributed to intestinal bacterium <i>Alistipes shahii</i>, which preferentially populates in females rather than males. <i>A. shahii</i>-associated metabolite lurasidone directly targets iron sequestrator LCN2 in RLSNs. By freeing Fe<sup>2+</sup>, lurasidone induces ferroptosis, thereby eliminating RLSNs and promoting antitumor immunity in females. In males lacking <i>A. shahii</i> and lurasidone, RLSNs have a survival advantage. Together, these findings demonstrate that a microbiota–lurasidone–LCN2 circuit regulates sexual disparity in bladder cancer and indicates the therapeutic potential of lurasidone for male cancer patients.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"35 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819223","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":"Human immunology soars in Japan","authors":"Yuki Masuo, Dongyun Lu, Joey Matsuyama, Eui-Cheol Shin, Hideki Ueno","doi":"10.1038/s41590-025-02122-w","DOIUrl":"https://doi.org/10.1038/s41590-025-02122-w","url":null,"abstract":"To address the increasing importance of studying immunology in humans, rather than a reliance on model systems, back-to-back symposia highlighting advances in human immunology were held in Osaka and Kyoto in Japan.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"33 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775324","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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