Nature Immunology最新文献

{"title":"Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells","authors":"Linda V. Sinclair, Tom Youdale, Laura Spinelli, Milica Gakovic, Alistair J. Langlands, Shalini Pathak, Andrew J. M. Howden, Ian G. Ganley, Doreen A. Cantrell","doi":"10.1038/s41590-025-02090-1","DOIUrl":"10.1038/s41590-025-02090-1","url":null,"abstract":"Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive T cells, mitophagy dominates and selective mitochondrial pruning supports the expression of molecules that coordinate T cell migration and survival. Autophagy thus differentially prunes naive and effector T cell proteomes and is dynamically repressed by antigen receptors and inflammatory cytokines to shape T cell differentiation. Sinclair et al. combine quantitative proteomics and an autophagy flux reporter to map autophagy substrates and triggers during CD8 T cell differentiation. Proteins degraded and fueled by autophagy in naïve and effector T cells are identified and it is revealed that the regulation of amino acid transport allows antigen receptors and inflammatory cytokines to repress autophagy flux to shape T cell differentiation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 3","pages":"429-443"},"PeriodicalIF":27.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-025-02090-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507098","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}

{"title":"Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing","authors":"Tomer Itkin, Sean Houghton, Ryan Schreiner, Yang Lin, Chaitanya R. Badwe, Veronique Voisin, Alex Murison, Negar Seyedhassantehrani, Kerstin B. Kaufmann, Laura Garcia-Prat, Gregory T. Booth, Fuqiang Geng, Ying Liu, Jesus M. Gomez-Salinero, Jae-Hung Shieh, David Redmond, Jenny Z. Xiang, Steven Z. Josefowicz, Cole Trapnell, Eric M. Pietras, Joel A. Spencer, Ross Levine, Wenbin Xiao, Lior Zangi, Brandon Hadland, John E. Dick, Stephanie Z. Xie, Shahin Rafii","doi":"10.1038/s41590-025-02087-w","DOIUrl":"10.1038/s41590-025-02087-w","url":null,"abstract":"Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined. Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation. Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine. Itkin et al. identify a role for Fli-1 in hematopoietic stem cell activation during regenerative hematopoiesis. They show that Fli-1 coordinates hematopoietic stem cells to stimulate niche-derived Notch1 feedback signals for demand-needed hematopoietic cell output.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 3","pages":"378-390"},"PeriodicalIF":27.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-025-02087-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485666","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}

{"title":"Calcium signaling is essential for T helper 1 cell differentiation","authors":"","doi":"10.1038/s41590-025-02101-1","DOIUrl":"10.1038/s41590-025-02101-1","url":null,"abstract":"Store-operated calcium entry in CD4+ T helper cells is essential for activation of the transcription factor NFAT, which promotes expression of the T helper 1 cell-lineage-determining transcription factor T-bet. We show that NFAT synergizes with interferon-induced STAT1 to drive T-bet expression in the absence of IL-12 signaling.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 3","pages":"349-350"},"PeriodicalIF":27.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-025-02101-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485662","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}

{"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":"10.1038/s41590-025-02102-0","url":null,"abstract":"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. In this Review, Matarese and colleagues discuss how immunometabolism controls the physiology and pathophysiology of B cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 3","pages":"366-377"},"PeriodicalIF":27.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-025-02102-0.pdf","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":"OA","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":"10.1038/s41590-025-02089-8","url":null,"abstract":"Stromal interaction molecule 1 (STIM1) is critical for store-operated Ca2+ entry (SOCE) and T cell activation. T helper 1 (TH1) cells, which express T-bet (encoded by TBX21), mediate immunity to intracellular pathogens. Although SOCE is known to regulate other TH lineages, its role in Th1 differentiation remains unclear. Here, we report a patient with an intronic loss-of-function mutation in STIM1, 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 TBX21 enhancer and enables NFAT to synergize with STAT1 to mediate TBX21 expression. While SOCE-deficient CD4+ T cells have reduced expression of TBX21 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. Feske and colleagues show how STIM- and ORAI-dependent calcium activation of NFAT plus IFN–STAT1 signaling activates T-bet expression independently of IL-12 stimulation. This NFAT–STAT1 activation pathway is required for TH1 cell differentiation and protection against viral infections when IL-12 is missing.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 3","pages":"484-496"},"PeriodicalIF":27.7,"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":"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":"26 3","pages":"337-339"},"PeriodicalIF":27.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-025-02093-y.pdf","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":"OA","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":"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":"26 3","pages":"345-346"},"PeriodicalIF":27.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-025-02098-7.pdf","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":"OA","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":"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":"26 3","pages":"325-329"},"PeriodicalIF":27.7,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-025-02092-z.pdf","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":"OA","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":"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":"26 3","pages":"347-348"},"PeriodicalIF":27.7,"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":"10.1038/s41590-025-02088-9","url":null,"abstract":"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. Gain-of-function variants in the gene encoding NLRP3 lead to constitutive inflammasome activation and excessive IL-1β production. In this resource, authors perform functional screening of clinically relevant NLRP3 variants. Structural analysis suggested multiple mechanisms by which variants activate NLRP3 and the identification of pathogenic variants that can sensitize the activation of NLRP3 in response to nigericin and cold temperature exposure.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"26 3","pages":"511-523"},"PeriodicalIF":27.7,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-025-02088-9.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}