IF 32.4 1区医学

Immunity Pub Date : 2025-05-16 DOI: 10.1016/j.immuni.2025.04.028

Qiwu Bian, Yihang Chen, Jinghe Zhang, Xianghui Du, Yonggang Zhou, Qiao Zhang, Chen Ding, Haiming Wei, Binqing Fu

{"title":"Maternal natural killer cells drive neuroimmune disorders in offspring through aberrant secretion of extracellular granzyme B","authors":"Qiwu Bian, Yihang Chen, Jinghe Zhang, Xianghui Du, Yonggang Zhou, Qiao Zhang, Chen Ding, Haiming Wei, Binqing Fu","doi":"10.1016/j.immuni.2025.04.028","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.028","url":null,"abstract":"Prenatal viral infections can lead to neurodevelopmental disorders in offspring. However, how viral-induced maternal perturbations impact fetal brain macrophages remains insufficiently clear. Here, we demonstrated that inflammatory decidual natural killer (NK) cells, triggered by viral infection-induced maternal immune activation, drove macrophage activation, neurodevelopmental disorders, and behavioral deficits in offspring. Extracellular granzyme B (GzmB), predominantly released by the maternal CD49a+ tissue-resident NK subset under type I interferon stimulation, crossed the maternal-fetal barrier and promoted interferon-stimulated gene (ISG)-expressing fetal macrophage accumulation and microglial activation. Targeting extracellular GzmB through the systemic administration of the serine protease inhibitor Serpina3n or genetic ablation of Gzmb in maternal NK cells mitigated neuroimmune disorders in the fetal brain. These findings suggest that exposure to a perturbed maternal milieu reprograms decidual NK cell immunity, disrupting fetal neuroimmune homeostasis and increasing offspring susceptibility to neurodevelopmental disorders later in life.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"124 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065975","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}

引用次数: 0

Glycosylation-driven programs coordinate immunoregulatory and pro-angiogenic functions of myeloid-derived suppressor cells 糖基化驱动程序协调骨髓源性抑制细胞的免疫调节和促血管生成功能

IF 32.4 1区医学

Immunity Pub Date : 2025-05-16 DOI: 10.1016/j.immuni.2025.04.027

Ada G. Blidner, Camila A. Bach, Pablo A. García, Joaquín P. Merlo, Alejandro J. Cagnoni, Nadia Bannoud, Montana N. Manselle Cocco, Juan M. Pérez Sáez, Nicolás A. Pinto, Nicolás I. Torres, Luciana Sarrias, Tomás Dalotto-Moreno, Sabrina G. Gatto, Rosa M. Morales, M. Laura Giribaldi, Juan C. Stupirski, Juan P. Cerliani, Susan L. Bellis, Mariana Salatino, María F. Troncoso, Gabriel A. Rabinovich

{"title":"Glycosylation-driven programs coordinate immunoregulatory and pro-angiogenic functions of myeloid-derived suppressor cells","authors":"Ada G. Blidner, Camila A. Bach, Pablo A. García, Joaquín P. Merlo, Alejandro J. Cagnoni, Nadia Bannoud, Montana N. Manselle Cocco, Juan M. Pérez Sáez, Nicolás A. Pinto, Nicolás I. Torres, Luciana Sarrias, Tomás Dalotto-Moreno, Sabrina G. Gatto, Rosa M. Morales, M. Laura Giribaldi, Juan C. Stupirski, Juan P. Cerliani, Susan L. Bellis, Mariana Salatino, María F. Troncoso, Gabriel A. Rabinovich","doi":"10.1016/j.immuni.2025.04.027","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.027","url":null,"abstract":"Myeloid-derived suppressor cells (MDSCs) promote tumor progression by suppressing antitumor immunity and inducing angiogenesis; however, the mechanisms linking these processes remain uncertain. Here, we identified a glycosylation-dependent program driven by galectin-1 (GAL1) that imparted both immunoregulatory and pro-angiogenic functions to MDSCs through shared receptor signaling pathways. GAL1 expression was associated with enhanced MDSC phenotypes and poor prognosis in diverse human cancers. Analysis of monocytic and polymorphonuclear MDSCs from tumor-bearing mice revealed niche-specific glycan signatures that selectively regulated GAL1 binding. Through glycosylation-dependent interactions with the CD18-CD11b-CD177 receptor complex and STAT3 signaling, GAL1 simultaneously orchestrated immunosuppressive and pro-angiogenic programs in MDSCs, driving tumor growth in vivo. Myeloid-specific deletion of β-galactoside α(2,6)-sialyltransferase 1, which prevented α(2,6)-linked sialic acid incorporation, enhanced GAL1-driven regulatory circuits and accelerated tumor progression, effects that were mitigated by GAL1-neutralizing antibodies. Thus, targeting GAL1-glycan interactions may offer opportunities to reprogram MDSCs and enhance the efficacy of immunotherapeutic and anti-angiogenic strategies.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"52 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065974","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}

引用次数: 0

Heterozygosity for Crohn’s disease risk allele of ATG16L1 promotes unique protein interactions and protects against bacterial infection 克罗恩病风险等位基因ATG16L1的杂合性促进独特的蛋白质相互作用并保护免受细菌感染

IF 32.4 1区医学

Immunity Pub Date : 2025-05-14 DOI: 10.1016/j.immuni.2025.04.023

Xiaomin Yao, Eugene Rudensky, Patricia K. Martin, Brittany M. Miller, Isabel Vargas, Erin E. Zwack, Keenan A. Lacey, Zhengxiang He, Glaucia C. Furtado, Sérgio A. Lira, Victor J. Torres, Bo Shopsin, Ken Cadwell

{"title":"Heterozygosity for Crohn’s disease risk allele of ATG16L1 promotes unique protein interactions and protects against bacterial infection","authors":"Xiaomin Yao, Eugene Rudensky, Patricia K. Martin, Brittany M. Miller, Isabel Vargas, Erin E. Zwack, Keenan A. Lacey, Zhengxiang He, Glaucia C. Furtado, Sérgio A. Lira, Victor J. Torres, Bo Shopsin, Ken Cadwell","doi":"10.1016/j.immuni.2025.04.023","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.023","url":null,"abstract":"The T300A substitution in ATG16L1 associated with Crohn’s disease impairs autophagy, yet up to 50% of humans are heterozygous for this allele. Here, we demonstrate that heterozygosity for the analogous substitution in mice (Atg16L1T316A), but not homozygosity, protects against lethal Salmonella enterica Typhimurium infection. One copy of Atg16L1T316A was sufficient to enhance cytokine production through inflammasome activation, which was necessary for protection. In contrast, two copies of Atg16L1T316A inhibited the autophagy-related process of LC3-associated phagocytosis (LAP) and increased susceptibility. Macrophages from human donors heterozygous for ATG16L1T300A displayed elevated inflammasome activation while homozygosity impaired LAP, similar to mice. These results clarify how the T300A substitution impacts ATG16L1 function and suggest it can be beneficial to heterozygous carriers, providing an explanation for its prevalence within the human population.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"20 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946285","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}

引用次数: 0

Microglial TMEM119 binds to amyloid-β to promote its clearance in an Aβ-depositing mouse model of Alzheimer’s disease 在阿尔茨海默病a β沉积小鼠模型中，小胶质细胞TMEM119结合淀粉样蛋白-β促进其清除

IF 32.4 1区医学

Immunity Pub Date : 2025-05-14 DOI: 10.1016/j.immuni.2025.04.018

Jing Liu, Zhimeng Wang, Wenwen Liang, Zhenhao Zhang, Yusen Deng, Xiaowei Chen, Zongren Hou, Yuanzhi Xie, Qi Wang, Yuan Li, Chaobo Bai, Da Li, Fan Mo, Huinan Wang, Dongmei Wang, Junliang Yuan, Yukai Wang, Zhao-Qian Teng, Baoyang Hu

{"title":"Microglial TMEM119 binds to amyloid-β to promote its clearance in an Aβ-depositing mouse model of Alzheimer’s disease","authors":"Jing Liu, Zhimeng Wang, Wenwen Liang, Zhenhao Zhang, Yusen Deng, Xiaowei Chen, Zongren Hou, Yuanzhi Xie, Qi Wang, Yuan Li, Chaobo Bai, Da Li, Fan Mo, Huinan Wang, Dongmei Wang, Junliang Yuan, Yukai Wang, Zhao-Qian Teng, Baoyang Hu","doi":"10.1016/j.immuni.2025.04.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.018","url":null,"abstract":"The progression of Alzheimer’s disease (AD) involves temporal dynamics of microglial activation. Restoring or maintaining microglial homeostasis has emerged as a promising therapeutic strategy to combat AD. Transmembrane protein 119 (TMEM119) is a homeostatic marker of microglia but has not been fully studied under AD pathological conditions. Here, we observed that amyloid-beta (Aβ) induced a decrease in TMEM119 expression in microglia, and TMEM119 deficiency increased AD progression in the 5×FAD mouse model. TMEM119 bound to Aβ oligomers and recruited low-density lipoprotein receptor 1, which in turn degraded TMEM119 itself. Overexpression of TMEM119 in microglia enhanced their phagocytic activity and alleviated cognitive deficits in 5xFAD mice. Administration of the small molecules Kartogenin and SRI-011381, which we found enhanced TMEM119 expression, substantially promoted Aβ clearance and improved cognitive function in AD mice, even during the mid-stage of the disease. These findings identify TMEM119 as a promising therapeutic target for AD.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"29 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946287","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}

引用次数: 0

nACh receptors engage a nice ChAT with the liver: B cells serving up regeneration nACh受体与肝脏进行良好的ChAT: B细胞提供再生

IF 32.4 1区医学

Immunity Pub Date : 2025-05-13 DOI: 10.1016/j.immuni.2025.04.021

Christoph Schultheiß, Mascha Binder

引用次数: 0

You know my NAMs 你知道我的名字

IF 32.4 1区医学

Immunity Pub Date : 2025-05-13 DOI: 10.1016/j.immuni.2025.04.025

Sourav Ghosh, Carla V. Rothlin

引用次数: 0

Dietary fuel or fire: Fatty acids rewire gut ILC3s 饮食燃料或火：脂肪酸重新连接肠道ilc3

IF 32.4 1区医学

Immunity Pub Date : 2025-05-13 DOI: 10.1016/j.immuni.2025.04.019

Qixiang Zhao, Changtao Jiang

引用次数: 0

Personalized syringes offer hope for pancreatic cancer patients 个性化注射器为胰腺癌患者带来希望

IF 32.4 1区医学

Immunity Pub Date : 2025-05-13 DOI: 10.1016/j.immuni.2025.04.026

Longling Silvia Shui, Peter M.K. Westcott

引用次数: 0

Pre-existing epigenetic state and differential NF-κB activation shape type 2 immune cell responses 预先存在的表观遗传状态和差异NF-κB激活形成2型免疫细胞反应

IF 32.4 1区医学

Immunity Pub Date : 2025-05-13 DOI: 10.1016/j.immuni.2025.04.016

Vincent Guichard, Felipe Batista Leão, Jingyao Zhao, Yingyu Zhang, Takamasa Ito, Simon Shirley, Thomas S. Postler, Ruxiao Tian, Yuefeng Huang, Sankar Ghosh

{"title":"Pre-existing epigenetic state and differential NF-κB activation shape type 2 immune cell responses","authors":"Vincent Guichard, Felipe Batista Leão, Jingyao Zhao, Yingyu Zhang, Takamasa Ito, Simon Shirley, Thomas S. Postler, Ruxiao Tian, Yuefeng Huang, Sankar Ghosh","doi":"10.1016/j.immuni.2025.04.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.016","url":null,"abstract":"CD4+ T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s) drive type 2 immune responses via similar effector molecules that are primarily induced by different signals—interleukin (IL)-33 in ILC2s and TCR engagement in Th2 cells. Here, we examined the transcriptional regulation of type 2 immunity, focusing on the NF-κB pathway, which is differentially activated by TCR engagement or cytokine signaling. Conditional deletion of the NF-κB subunits c-Rel and p65 limited the expression of key type 2 genes, including Il13 and Il5, in ILC2s but not in Th2 cells. Genome-wide analysis revealed that the regulatory regions of such genes exist in an open chromatin state in ILC2s, allowing NF-κB binding upon IL-33 stimulation. These regions are less accessible in unstimulated Th2 cells, where NFAT plays a dominant role. Accordingly, p65 deletion impaired ILC2 activation and function during airway inflammation and helminth infection. Thus, innate and adaptive lymphocytes leverage distinct epigenetic landscapes and transcriptional regulators to control shared effector genes.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"55 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940149","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}

引用次数: 0

Sickle cell disease induces chromatin introversion and ferroptosis in CD8+ T cells to suppress anti-tumor immunity 镰状细胞病诱导CD8+ T细胞染色质内向和铁下垂抑制抗肿瘤免疫

IF 32.4 1区医学

Immunity Pub Date : 2025-05-12 DOI: 10.1016/j.immuni.2025.04.020

Zilong Zhao, Benxia Hu, Yalan Deng, Melinda Soeung, Jun Yao, Lanxin Bei, Yaohua Zhang, Pengju Gong, Lisa A. Huang, Zhou Jiang, Jian Gao, Shuang Peng, Tina K. Nguyen, Menuka Karki, Bora Lim, Cassian Yee, Jared K. Burks, Qing Zhang, Li Ma, Jianjun Gao, Chunru Lin

{"title":"Sickle cell disease induces chromatin introversion and ferroptosis in CD8+ T cells to suppress anti-tumor immunity","authors":"Zilong Zhao, Benxia Hu, Yalan Deng, Melinda Soeung, Jun Yao, Lanxin Bei, Yaohua Zhang, Pengju Gong, Lisa A. Huang, Zhou Jiang, Jian Gao, Shuang Peng, Tina K. Nguyen, Menuka Karki, Bora Lim, Cassian Yee, Jared K. Burks, Qing Zhang, Li Ma, Jianjun Gao, Chunru Lin","doi":"10.1016/j.immuni.2025.04.020","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.04.020","url":null,"abstract":"Understanding how genetic disorders affect CD8+ T cells in the tumor microenvironment is key to improving cancer immunotherapy. Individuals with sickle cell disease (SCD), the most prevalent inherited blood disorder, have a higher risk of developing certain cancers than the general population, but the mechanisms driving this increased risk remain unclear. Our study revealed that SCD altered CD8+ T cell 3D genome architecture, triggering ferroptosis and weakening anti-tumor immunity, thereby promoting tumor growth. Using murine and humanized SCD models, we found that disrupted chromosomal interactions in CD8+ T cells reduced the expression of anti-ferroptotic genes, including SLC7A11 and hydrogen sulfide (H2S) biogenesis genes, thereby increasing susceptibility to ferroptosis. Therapeutic restoration of H2S concentration in SCD mice rescued SLC7A11 expression, mitigated ferroptosis, and enhanced immune and anti-tumor responses. These findings highlight the impact of inherited disorders on cancer immunity and suggest precision immunotherapy strategies for affected individuals.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"137 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933480","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}

引用次数: 0

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