Nature Immunology最新文献

{"title":"B cell immunometabolism in health and disease","authors":"Eleonora Martinis, Silvia Tonon, Alessandra Colamatteo, Antonio La Cava, Giuseppe Matarese, Carlo Ennio Michele Pucillo","doi":"10.1038/s41590-025-02102-0","DOIUrl":"https://doi.org/10.1038/s41590-025-02102-0","url":null,"abstract":"<p>B cells have crucial roles in the initiation and progression of many pathological conditions, and several therapeutic strategies have targeted the function of these cells. The advent of immunometabolism has provided compelling evidence that the metabolic reprogramming of immune cells can dramatically alter physiopathological immune activities. A better knowledge of the metabolic profiles of B cells can provide valuable means for developing therapies tuning defined cell pathways. Here we review the cellular and molecular mechanisms by which immunometabolism controls the physiology and pathophysiology of B cells and discuss the experimental evidence linking B cell metabolism to health, autoimmunity, and cancer. Considering that several metabolic pathways in B cells are involved differently, or even in opposite ways, in health and disease, we discuss how targeted modulation of B cell immunometabolism could be exploited mechanistically to rebalance abnormal B cell functions that have become altered in disease states.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"67 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462168","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":"STIM1-mediated NFAT signaling synergizes with STAT1 to control T-bet expression and TH1 differentiation","authors":"Li Zhong, Yin-Hu Wang, Sascha Kahlfuss, Miki Jishage, Maxwell McDermott, Jun Yang, Anthony Y. Tao, Ke Hu, Lucile Noyer, Dimitrius Raphael, Devisha Patel, Tristan E. Knight, Meera Chitlur, Khaled Machaca, Stefan Feske","doi":"10.1038/s41590-025-02089-8","DOIUrl":"https://doi.org/10.1038/s41590-025-02089-8","url":null,"abstract":"<p>Stromal interaction molecule 1 (STIM1) is critical for store-operated Ca²⁺ entry (SOCE) and T cell activation. T helper 1 (T_H1) cells, which express T-bet (encoded by <i>TBX21</i>), mediate immunity to intracellular pathogens. Although SOCE is known to regulate other T_H lineages, its role in Th1 differentiation remains unclear. Here, we report a patient with an intronic loss-of-function mutation in <i>STIM1</i>, which abolishes SOCE and causes immunodeficiency. We demonstrate that SOCE promotes nuclear factor of activated T cells (NFAT) binding to conserved noncoding sequence (CNS)-12 in the <i>TBX21</i> enhancer and enables NFAT to synergize with STAT1 to mediate <i>TBX21</i> expression. While SOCE-deficient CD4⁺ T cells have reduced expression of <i>TBX21</i> in the absence of interleukin-12 (IL-12), their expression of IL-12 receptors β1 and β2 is increased, sensitizing them to IL-12 signaling and allowing IL-12 to rescue T-bet expression. Our study reveals that the STIM1-SOCE–NFAT signaling axis is essential for the differentiation of Th1 cells depending on the cytokine milieu.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"20 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462167","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":"Functional analysis of NLRP3 variants provides insight into inflammasome regulation","authors":"Bénédicte F. Py","doi":"10.1038/s41590-025-02093-y","DOIUrl":"https://doi.org/10.1038/s41590-025-02093-y","url":null,"abstract":"Automated functional profiling of all natural NLRP3 variants accelerates the diagnosis of NLRP3-associated inflammatory diseases by classifying pathogenic mutants, and identifies key structural motifs for inflammasome regulation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"81 3 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451838","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":"Functional signatures and activation mechanisms of effector γδ T cell subsets","authors":"","doi":"10.1038/s41590-025-02098-7","DOIUrl":"https://doi.org/10.1038/s41590-025-02098-7","url":null,"abstract":"Genome-wide transcriptomics analysis of IFNγ-producing or IL-17A-producing γδ T cell subpopulations reveals marked differences in their mode of activation and functional potential in the periphery. We describe the differential expression of a set of 20 signature genes in models of infection and autoimmunity that may be useful for future studies on γδ T cell functions.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"64 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435071","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":"Systems neuroimmunology: current bottlenecks, research priorities and future directions","authors":"Harini Iyer, Christophe Benoist, Staci D. Bilbo, Lisa M. Boulanger, Michael D. Burton, Brian P. Daniels, Aleksandra Deczkowska, Martin F. Flajnik, Mélanie G. Gareau, Peter M. Grace, Javier E. Irazoqui, Susanna Rosi, Irene Salinas, Anne Schaefer, Caroline L. Sokol, Dionna W. Williams, Robyn S. Klein","doi":"10.1038/s41590-025-02092-z","DOIUrl":"https://doi.org/10.1038/s41590-025-02092-z","url":null,"abstract":"Strategies to advance the field of neuroimmunology by embracing its complexity via inclusion of its multidisciplinary properties were discussed at a meeting in Cold Spring Harbor. Attendees proposed fostering of open communications and funding of collaborations across disciplines, and the recognition that our understanding of the neuroimmune system requires interdisciplinary science.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"22 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393015","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":"Metabolite signaling promotes the recruitment of immunosuppressive cells to tumors","authors":"","doi":"10.1038/s41590-025-02094-x","DOIUrl":"https://doi.org/10.1038/s41590-025-02094-x","url":null,"abstract":"Metabolite-sensing G protein-coupled receptors act as critical signaling hubs that connect metabolism to immunity in cancer. Here we show that activation of the lactate receptor HCAR1 in colorectal tumor cells leads to the recruitment of immunosuppressive PMN-MDSCs to tumors, thereby impairing anti-tumor immunity and diminishing the effectiveness of immunotherapies.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"51 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375808","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":"Mechanisms of NLRP3 activation and inhibition elucidated by functional analysis of disease-associated variants","authors":"Shouya Feng, Matthew C. Wierzbowski, Katja Hrovat-Schaale, Andreas Dumortier, Yaoyuan Zhang, Maria Zyulina, Paul J. Baker, Thomas Reygaerts, Annemarie Steiner, Dominic De Nardo, Dhanya Lakshmi Narayanan, Florian Milhavet, Alberto Pinzon-Charry, Juan Ignacio Arostegui, Raju P. Khubchandani, Matthias Geyer, Guilaine Boursier, Seth L. Masters","doi":"10.1038/s41590-025-02088-9","DOIUrl":"https://doi.org/10.1038/s41590-025-02088-9","url":null,"abstract":"<p>The NLRP3 inflammasome is a multiprotein complex that mediates caspase-1 activation and the release of proinflammatory cytokines, including interleukin (IL)-1β and IL-18. Gain-of-function variants in the gene encoding NLRP3 (also called cryopyrin) lead to constitutive inflammasome activation and excessive IL-1β production in cryopyrin-associated periodic syndromes (CAPS). Here we present functional screening and automated analysis of 534 NLRP3 variants from the international INFEVERS registry and the ClinVar database. This resource captures the effect of NLRP3 variants on ASC speck formation spontaneously, at low temperature, after inflammasome stimulation and with the specific NLRP3 inhibitor MCC950. Most notably, our analysis facilitated the updated classification of NLRP3 variants in INFEVERS. Structural analysis suggested multiple mechanisms by which CAPS variants activate NLRP3, including enhanced ATP binding, stabilizing the active NLRP3 conformation, destabilizing the inactive NLRP3 complex and promoting oligomerization of the pyrin domain. Furthermore, we identified pathogenic variants that can hypersensitize the activation of NLRP3 in response to nigericin and cold temperature exposure. We also found that most CAPS-related NLRP3 variants can be inhibited by MCC950; however, NLRP3 variants with changes to proline affecting helices near the inhibitor binding site are resistant to MCC950, as are variants in the pyrin domain, which likely trigger activation directly with the pyrin domain of ASC. Our findings could help stratify the CAPS population for NLRP3 inhibitor clinical trials and our automated methodologies can be implemented for molecules with a different mechanism of activation and in laboratories worldwide that are interested in adding new functionally validated NLRP3 variants to the resource. Overall, our study provides improved diagnosis for patients with CAPS, mechanistic insight into the activation of NLRP3 and stratification of patients for the future application of targeted therapeutics.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"29 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375809","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":"Author Correction: β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus","authors":"Nargis Khan, Kim A. Tran, Raphael Chevre, Veronica Locher, Mathis Richter, Sarah Sun, Mina Sadeghi, Erwan Pernet, Andrea Herrero-Cervera, Alexandre Grant, Ahmed Saif, Jeffrey Downey, Eva Kaufmann, Shabaana Abdul Khader, Philippe Joubert, Luis B. Barreiro, Bryan G. Yipp, Oliver Soehnlein, Maziar Divangahi","doi":"10.1038/s41590-025-02099-6","DOIUrl":"https://doi.org/10.1038/s41590-025-02099-6","url":null,"abstract":"<p>Correction to: <i>Nature Immunology</i> https://doi.org/10.1038/s41590-024-02041-2, published online 8 January 2025.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"9 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367250","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":"Insights into autoimmunity and cancer","authors":"Xinrui Li, Carmen Ufret-Vincenty, Jacqueline Robinson-Hamm, Lillian Kuo, Heiyoung Park, Victoria K. Shanmugam","doi":"10.1038/s41590-025-02078-x","DOIUrl":"https://doi.org/10.1038/s41590-025-02078-x","url":null,"abstract":"In December 2024, the NIH Office of Autoimmune Disease Research in the Office of Research on Women’s Health (OADR-ORWH) hosted a virtual meeting in the ScienceTALKS series entitled ‘The Cancer Autoimmune Connection: Decoding the Paradox’.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"15 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257887","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":"The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer","authors":"Jiacheng He, Xiaolei Chai, Qiansen Zhang, Yang Wang, Yijie Wang, Xinyu Yang, Jingbo Wu, Bo Feng, Jing Sun, Weiwei Rui, Shuyin Ze, Yuanyuan Fu, Yumiao Zhao, Ying Zhang, Yao Zhang, Meizhen Liu, Chuang Liu, Meifu She, Xiangfei Hu, Xueyun Ma, Huaiyu Yang, Dawei Li, Senlin Zhao, Guichao Li, Zhen Zhang, Zhonghui Tian, Yanlin Ma, Lingyan Cao, Bo Yi, Dali Li, Ruth Nussinov, Charis Eng, Timothy A. Chan, Eytan Ruppin, J. Silvio Gutkind, Feixiong Cheng, Mingyao Liu, Weiqiang Lu","doi":"10.1038/s41590-024-02068-5","DOIUrl":"https://doi.org/10.1038/s41590-024-02068-5","url":null,"abstract":"<p>Most patients with colorectal cancer do not achieve durable clinical benefits from immunotherapy, underscoring the existence of alternative immunosuppressive mechanisms. Here we found that activation of the lactate receptor HCAR1 signaling pathway induced the expression of chemokines CCL2 and CCL7 in colorectal tumor cells, leading to the recruitment of immunosuppressive CCR2⁺ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment. Ablation of <i>Hcar1</i> in mice with colorectal tumors significantly decreased the abundance of tumor-infiltrating CCR2⁺ PMN-MDSCs, enhanced the activation of CD8⁺ T cells and, consequently, reduced tumor burden. We detected immunosuppressive CCR2⁺ PMN-MDSCs in tumor specimens from individuals with colorectal and other cancers. The US Food and Drug Administration-approved drug reserpine suppressed lactate-mediated HCAR1 activation, impaired the recruitment of CCR2⁺ PMN-MDSCs, boosted CD8⁺ T cell-dependent antitumor immunity and sensitized immunotherapy-resistant tumors to programmed cell death protein 1 antibody therapy in mice with colorectal tumors. Altogether, we described HCAR1-driven recruitment of CCR2⁺ PMN-MDSCs as a mechanism of immunosuppression.</p>","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"76 2 1","pages":""},"PeriodicalIF":30.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083423","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}