Nature Immunology最新文献

{"title":"Targeting p97–Npl4 interaction inhibits tumor Treg cell development to enhance tumor immunity","authors":"Pingping Nie, Zhifa Cao, Ruixian Yu, Chao Dong, Weihong Zhang, Yan Meng, Hui Zhang, Yu Pan, Zhenzhu Tong, Xiaoya Jiang, Shilong Wang, Mengwen Zhu, Yi Han, Wenjia Wang, Yiming Zhang, Lijie Tan, Chuanchuan Li, Yuanzhi Xu, Liwei An, Bin Li, Shi Jiao, Zhaocai Zhou","doi":"10.1038/s41590-024-01912-y","DOIUrl":"10.1038/s41590-024-01912-y","url":null,"abstract":"Targeting tumor-infiltrating regulatory T (TI-Treg) cells is a potential strategy for cancer therapy. The ATPase p97 in complex with cofactors (such as Npl4) has been investigated as an antitumor drug target; however, it is unclear whether p97 has a function in immune cells or immunotherapy. Here we show that thonzonium bromide is an inhibitor of the interaction of p97 and Npl4 and that this p97–Npl4 complex has a critical function in TI-Treg cells. Thonzonium bromide boosts antitumor immunity without affecting peripheral Treg cell homeostasis. The p97–Npl4 complex bridges Stat3 with E3 ligases PDLIM2 and PDLIM5, thereby promoting Stat3 degradation and enabling TI-Treg cell development. Collectively, this work shows an important role for the p97–Npl4 complex in controlling Treg–TH17 cell balance in tumors and identifies possible targets for immunotherapy. Tumor-infiltrating regulatory T (TI-Treg) cells help tumor growth by suppressing local immune responses. Here the authors show that thonzonium bromide can help fight tumors by interfering with the interaction of p97 and Npl4, a complex that they show supports TI-Treg cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895195","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":"Nucleophosmin 1 promotes mucosal immunity by supporting mitochondrial oxidative phosphorylation and ILC3 activity","authors":"Rongchuan Zhao, Jiao Yang, Yunjiao Zhai, Hong Zhang, Yuanshuai Zhou, Lei Hong, Detian Yuan, Ruilong Xia, Yanxiang Liu, Jinlin Pan, Shaheryar Shafi, Guohua Shi, Ruobing Zhang, Dingsan Luo, Jinyun Yuan, Dejing Pan, Changgeng Peng, Shiyang Li, Minxuan Sun","doi":"10.1038/s41590-024-01921-x","DOIUrl":"10.1038/s41590-024-01921-x","url":null,"abstract":"Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1+/− mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis. Given associations between colitis and myelodysplastic syndrome (in which nucleophosmin 1 is often mutated), the authors here look at the contribution of nucleophosmin 1 to colitis, showing that it is important for protection mediated by ILC3s owing to effects on mitochondrial metabolism.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01921-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893870","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":"IFN versus AHR-JUN","authors":"Laurie A. Dempsey","doi":"10.1038/s41590-024-01927-5","DOIUrl":"10.1038/s41590-024-01927-5","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860391","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":"Triads fight tumors","authors":"Nicholas J. Bernard","doi":"10.1038/s41590-024-01929-3","DOIUrl":"10.1038/s41590-024-01929-3","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860393","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":"Putting the STING in MS","authors":"Stephanie Houston","doi":"10.1038/s41590-024-01930-w","DOIUrl":"10.1038/s41590-024-01930-w","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860392","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":"A unique serum IgG glycosylation signature predicts development of Crohn’s disease and is associated with pathogenic antibodies to mannose glycan","authors":"Joana Gaifem, Cláudia S. Rodrigues, Francesca Petralia, Inês Alves, Eduarda Leite-Gomes, Bruno Cavadas, Ana M. Dias, Catarina Moreira-Barbosa, Joana Revés, Renee M. Laird, Mislav Novokmet, Jerko Štambuk, Siniša Habazin, Berk Turhan, Zeynep H. Gümüş, Ryan Ungaro, Joana Torres, Gordan Lauc, Jean-Frederic Colombel, Chad K. Porter, Salomé S. Pinho","doi":"10.1038/s41590-024-01916-8","DOIUrl":"10.1038/s41590-024-01916-8","url":null,"abstract":"Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn’s disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome–ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome–ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention. Here the authors show that there are alterations in the glycome profile of serum IgG Fc regions that precede the diagnosis of Crohn’s disease by many years and are associated with complications during disease. This altered glycome triggers innate immune cell activation at a preclinical phase, which is the basis for the transition from healthy tissue to intestinal inflammation.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01916-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794609","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":"Author Correction: Elusive early NK cell progenitor identified","authors":"Emma Patey, Niklas K. Björkström","doi":"10.1038/s41590-024-01942-6","DOIUrl":"10.1038/s41590-024-01942-6","url":null,"abstract":"","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01942-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792893","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":"Directing risky traffic in B cells with TNIP1","authors":"Michael P. Cancro, Ann Marshak-Rothstein","doi":"10.1038/s41590-024-01913-x","DOIUrl":"10.1038/s41590-024-01913-x","url":null,"abstract":"TNIP1, a previously identified risk factor for autoimmunity, regulates mitochondrial autophagosomal trafficking. Missense mutations in TNIP1 disrupt this regulatory function, yielding a B cell-intrinsic predisposition for TLR7-mediated autoimmunity characterized by IgG4 autoantibodies and the expansion of age-associated B cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764361","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":"An intestinal TH17 cell-derived subset can initiate cancer","authors":"Olivier Fesneau, Valentin Thevin, Valérie Pinet, Chloe Goldsmith, Baptiste Vieille, Saïdi M’Homa Soudja, Rossano Lattanzio, Michael Hahne, Valérie Dardalhon, Hector Hernandez-Vargas, Nicolas Benech, Julien C. Marie","doi":"10.1038/s41590-024-01909-7","DOIUrl":"10.1038/s41590-024-01909-7","url":null,"abstract":"Approximately 25% of cancers are preceded by chronic inflammation that occurs at the site of tumor development. However, whether this multifactorial oncogenic process, which commonly occurs in the intestines, can be initiated by a specific immune cell population is unclear. Here, we show that an intestinal T cell subset, derived from interleukin-17 (IL-17)-producing helper T (TH17) cells, induces the spontaneous transformation of the intestinal epithelium. This subset produces inflammatory cytokines, and its tumorigenic potential is not dependent on IL-17 production but on the transcription factors KLF6 and T-BET and interferon-γ. The development of this cell type is inhibited by transforming growth factor-β1 (TGFβ1) produced by intestinal epithelial cells. TGFβ signaling acts on the pretumorigenic TH17 cell subset, preventing its progression to the tumorigenic stage by inhibiting KLF6-dependent T-BET expression. This study therefore identifies an intestinal T cell subset initiating cancer. Here, the authors show that there is a pretumorigenic TH17 subset in the intestines that can convert to being tumorigenic under the control of KLF6 and that this process can be prevented by TGFβ1 production from intestinal epithelial cells.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01909-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764359","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":"A TNIP1-driven systemic autoimmune disorder with elevated IgG4","authors":"Arti Medhavy, Vicki Athanasopoulos, Katharine Bassett, Yuke He, Maurice Stanley, Daniel Enosi Tuipulotu, Jean Cappello, Grant J. Brown, Paula Gonzalez-Figueroa, Cynthia Turnbull, Somasundhari Shanmuganandam, Padmaja Tummala, Gemma Hart, Tom Lea-Henry, Hao Wang, Sonia Nambadan, Qian Shen, Jonathan A. Roco, Gaetan Burgio, Phil Wu, Eun Cho, T. Daniel Andrews, Matt A. Field, Xiaoqian Wu, Huihua Ding, Qiang Guo, Nan Shen, Si Ming Man, Simon H. Jiang, Matthew C. Cook, Carola G. Vinuesa","doi":"10.1038/s41590-024-01902-0","DOIUrl":"10.1038/s41590-024-01902-0","url":null,"abstract":"Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-β without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics. Vinuesa et al. identify patients with systemic autoimmunity and a TNIP1 variant that result in dysregulated B cell function. Mice with the orthologous Tnip1 mutation develop spontaneous autoimmunity associated with impaired mitophagy and autophagic silencing of proteins downstream of Toll-like receptor 7 signaling.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01902-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764360","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}