Cellular &Molecular Immunology最新文献_第5页

Dysregulation in keratinocytes drives systemic lupus erythematosus onset 角化细胞失调驱动系统性红斑狼疮发病。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-12-03 DOI: 10.1038/s41423-024-01240-z

Jingru Tian, Liqing Shi, Dingyao Zhang, Xu Yao, Ming Zhao, Snehlata Kumari, Jun Lu, Di Yu, Qianjin Lu

{"title":"Dysregulation in keratinocytes drives systemic lupus erythematosus onset","authors":"Jingru Tian, Liqing Shi, Dingyao Zhang, Xu Yao, Ming Zhao, Snehlata Kumari, Jun Lu, Di Yu, Qianjin Lu","doi":"10.1038/s41423-024-01240-z","DOIUrl":"10.1038/s41423-024-01240-z","url":null,"abstract":"Systemic lupus erythematosus (SLE) is a complex, multiorgan autoimmune disorder. Although it is widely believed that SLE originates from immune cell dysregulation, the etiology of SLE is not yet clear. Here, we propose a new theory in which SLE can be directly initiated by molecular alterations in keratinocytes rather than immune cells. We found that the level of peroxisome proliferator-activated receptor gamma (PPARγ) is substantially reduced in the skin lesions of patients, and replicating this reduction in mice led to rapid disease onset with multiple hallmarks of SLE. As PPARγ decreases in keratinocytes, which is accompanied by increased occupancy of interferon regulatory factor 3 at the type I interferon locus, dendritic cells (DCs) are recruited to the epidermis and are activated by keratinocyte-secreted type I interferon. These activated DCs migrate to local draining lymph nodes, where they activate CD4+ T cells in a non-MHC II-dependent manner, promoting their differentiation into effector T cells and thus contributing to disease onset. Our study revealed that the dysregulation of keratinocytes can be a pathogenic driver of SLE and describes a new mouse model that mimics human SLE. Our data also emphasize the pivotal role of skin immunity in the onset of systemic autoimmune disease.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 1","pages":"83-96"},"PeriodicalIF":21.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766649","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

Dynamic O-GlcNAcylation governs long-range chromatin interactions in V(D)J recombination during early B-cell development 动态o - glcn酰化控制了早期b细胞发育过程中V(D)J重组过程中的远程染色质相互作用。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-12-03 DOI: 10.1038/s41423-024-01236-9

Bong Chan Jeon, Yu-Ji Kim, Ae Kyung Park, Mi-Ran Song, Ki Myeong Na, Juwon Lee, Dasom An, Yeseul Park, Heeyoun Hwang, Tae-Don Kim, Junghyun Lim, Sung-Kyun Park

{"title":"Dynamic O-GlcNAcylation governs long-range chromatin interactions in V(D)J recombination during early B-cell development","authors":"Bong Chan Jeon, Yu-Ji Kim, Ae Kyung Park, Mi-Ran Song, Ki Myeong Na, Juwon Lee, Dasom An, Yeseul Park, Heeyoun Hwang, Tae-Don Kim, Junghyun Lim, Sung-Kyun Park","doi":"10.1038/s41423-024-01236-9","DOIUrl":"10.1038/s41423-024-01236-9","url":null,"abstract":"V(D)J recombination secures the production of functional immunoglobulin (Ig) genes and antibody diversity during the early stages of B-cell development through long-distance interactions mediated by cis-regulatory elements and trans-acting factors. O-GlcNAcylation is a dynamic and reversible posttranslational modification of nuclear and cytoplasmic proteins that regulates various protein functions, including DNA-binding affinity and protein–protein interactions. However, the effects of O-GlcNAcylation on proteins involved in V(D)J recombination remain largely unknown. To elucidate this relationship, we downregulated O-GlcNAcylation in a mouse model by administering an O-GlcNAc inhibitor or restricting the consumption of a regular diet. Interestingly, the inhibition of O-GlcNAcylation in mice severely impaired Ig heavy-chain (IgH) gene rearrangement. We identified several factors crucial for V(D)J recombination, including YY1, CTCF, SMC1, and SMC3, as direct targets of O-GlcNAc modification. Importantly, O-GlcNAcylation regulates the physical interaction between SMC1 and SMC3 and the DNA-binding patterns of YY1 at the IgH gene locus. Moreover, O-GlcNAc inhibition downregulated DDX5 protein expression, affecting the functional association of CTCF with its DNA-binding sites at the IgH locus. Our results showed that locus contraction and long-range interactions throughout the IgH locus are disrupted in a manner dependent on the cellular O-GlcNAc level. In this study, we established that V(D)J recombination relies on the O-GlcNAc status of stage-specific proteins during early B-cell development and identified O-GlcNAc-dependent mechanisms as new regulatory components for the development of a diverse antibody repertoire.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 1","pages":"68-82"},"PeriodicalIF":21.8,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766635","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

Gasdermin D unlocks metabolic pathways to enhance tissue regeneration Gasdermin D 释放新陈代谢途径，促进组织再生。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-11-22 DOI: 10.1038/s41423-024-01239-6

Quazi T. H. Shubhra

引用次数: 0

Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation 由HIF-1α控制的代谢重新布线可调节产生IgA的B细胞分化和肠道炎症。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-11-14 DOI: 10.1038/s41423-024-01233-y

Xianyi Meng, Sahar Asadi-Asadabad, Shan Cao, Rui Song, Zhen Lin, Mohammed Safhi, Yi Qin, Estelle Tcheumi Tactoum, Verena Taudte, Arif Ekici, Dirk Mielenz, Stefan Wirtz, Georg Schett, Aline Bozec

{"title":"Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation","authors":"Xianyi Meng, Sahar Asadi-Asadabad, Shan Cao, Rui Song, Zhen Lin, Mohammed Safhi, Yi Qin, Estelle Tcheumi Tactoum, Verena Taudte, Arif Ekici, Dirk Mielenz, Stefan Wirtz, Georg Schett, Aline Bozec","doi":"10.1038/s41423-024-01233-y","DOIUrl":"10.1038/s41423-024-01233-y","url":null,"abstract":"Germinal centers where B cells undergo clonal expansion and antibody affinity maturation are hypoxic microenvironments. However, the function of hypoxia-inducible factor (HIF)-1α in immunoglobulin production remains incompletely characterized. Here, we demonstrated that B cells lacking HIF-1α exhibited significantly lower glycolytic metabolism and impaired IgA production. Loss of HIF-1α in B cells affects IgA-producing B-cell differentiation and exacerbates dextran sodium sulfate (DSS)-induced colitis. Conversely, promoting HIF-1α stabilization via a PHD inhibitor roxadustat enhances IgA class switching and alleviates intestinal inflammation. Mechanistically, HIF-1α facilitates IgA class switching through acetyl-coenzyme A (acetyl-CoA) accumulation, which is essential for histone H3K27 acetylation at the Sα region. Consequently, supplementation with acetyl-CoA improved defective IgA production in Hif1a-deficient B cells and limited experimental colitis. Collectively, these findings highlight the critical importance of HIF-1α in IgA class switching and the potential for targeting the HIF-1α-dependent metabolic‒epigenetic axis to treat inflammatory bowel diseases and other inflammatory disorders.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 1","pages":"54-67"},"PeriodicalIF":21.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01233-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615998","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}

引用次数: 0

Alternative mRNA polyadenylation regulates macrophage hyperactivation via the autophagy pathway 交替 mRNA 多腺苷酸化通过自噬途径调节巨噬细胞的过度激活。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-11-13 DOI: 10.1038/s41423-024-01237-8

Yunzhu Chen, Baiwen Chen, Jingyu Li, Haixin Li, Gaoyang Wang, Xuemin Cai, Qianqian Zhang, Xiaoxu Liu, Chen Kan, Lei Wang, Zhengting Wang, Hua-Bing Li

{"title":"Alternative mRNA polyadenylation regulates macrophage hyperactivation via the autophagy pathway","authors":"Yunzhu Chen, Baiwen Chen, Jingyu Li, Haixin Li, Gaoyang Wang, Xuemin Cai, Qianqian Zhang, Xiaoxu Liu, Chen Kan, Lei Wang, Zhengting Wang, Hua-Bing Li","doi":"10.1038/s41423-024-01237-8","DOIUrl":"10.1038/s41423-024-01237-8","url":null,"abstract":"Macrophage hyperactivation is a hallmark of inflammatory diseases, yet the role of alternative polyadenylation (APA) of mRNAs in regulating innate immunity remains unclear. In this study, we focused on 3’UTR-APA and demonstrated that Nudt21, a crucial RNA-binding component of the 3’UTR-APA machinery, is significantly upregulated in various inflammatory conditions. By utilizing myeloid-specific Nudt21-deficient mice, we revealed a protective effect of Nudt21 depletion against colitis and severe hyperinflammation, primarily through diminished production of proinflammatory cytokines. Notably, Nudt21 regulates the mRNA stability of key autophagy-related genes, Map1lc3b and Ulk2, by mediating selective 3’UTR polyadenylation in activated macrophages. As a result, Nudt21-deficient macrophages display increased autophagic activity, which leads to reduced cytokine secretion. Our findings highlight an unexplored role of Nudt21-mediated 3’UTR-APA in modulating macrophage autophagy and offer new insights into the modulation of inflammation and disease progression.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1522-1534"},"PeriodicalIF":21.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01237-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615993","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}

引用次数: 0

Critical and differential roles of eIF4A1 and eIF4A2 in B-cell development and function eIF4A1 和 eIF4A2 在 B 细胞发育和功能中的关键和不同作用。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-11-08 DOI: 10.1038/s41423-024-01234-x

Ying Du, Jun Xie, Dewang Liu, Jiayi Zhao, Pengda Chen, Xiaoyu He, Peicheng Hong, Yubing Fu, Yazhen Hong, Wen-Hsien Liu, Changchun Xiao

{"title":"Critical and differential roles of eIF4A1 and eIF4A2 in B-cell development and function","authors":"Ying Du, Jun Xie, Dewang Liu, Jiayi Zhao, Pengda Chen, Xiaoyu He, Peicheng Hong, Yubing Fu, Yazhen Hong, Wen-Hsien Liu, Changchun Xiao","doi":"10.1038/s41423-024-01234-x","DOIUrl":"10.1038/s41423-024-01234-x","url":null,"abstract":"Eukaryotic initiation factor 4 A (eIF4A) plays critical roles during translation initiation of cellular mRNAs by forming the cap-binding eIF4F complex, recruiting the 40S small ribosome subunit, and scanning the 5’ untranslated region (5’ UTR) for the start codon. eIF4A1 and eIF4A2, two isoforms of eIF4A, are highly conserved and exchange freely within eIF4F complexes. The understanding of their biological and molecular functions remains incomplete if not fragmentary. In this study, we showed that eIF4A1 and eIF4A2 exhibit different expression patterns during B-cell development and activation. Mouse genetic analyses showed that they play critical but differential roles during B-cell development and humoral immune responses. While eIF4A1 controls global protein synthesis, eIF4A2 regulates the biogenesis of 18S ribosomal RNA and the 40S ribosome subunit. This study demonstrates the distinct cellular and molecular functions of eIF4A1 and eIF4A2 and reveals a new role of eIF4A2 in controlling 40S ribosome biogenesis.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 1","pages":"40-53"},"PeriodicalIF":21.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01234-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615995","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}

引用次数: 0

Targeting of TAMs: can we be more clever than cancer cells? 靶向 TAMs：我们能比癌细胞更聪明吗？

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-11-08 DOI: 10.1038/s41423-024-01232-z

Julia Kzhyshkowska, Jiaxin Shen, Irina Larionova

{"title":"Targeting of TAMs: can we be more clever than cancer cells?","authors":"Julia Kzhyshkowska, Jiaxin Shen, Irina Larionova","doi":"10.1038/s41423-024-01232-z","DOIUrl":"10.1038/s41423-024-01232-z","url":null,"abstract":"With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1376-1409"},"PeriodicalIF":21.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01232-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615999","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}

引用次数: 0

Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma 靶向 GSDME 介导的巨噬细胞极化，增强肝细胞癌的抗肿瘤免疫力。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-11-04 DOI: 10.1038/s41423-024-01231-0

Shiping Chen, Peiling Zhang, Guiqi Zhu, Biao Wang, Jialiang Cai, Lina Song, Jinglei Wan, Yi Yang, Junxian Du, Yufan Cai, Jian Zhou, Jia Fan, Zhi Dai

{"title":"Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma","authors":"Shiping Chen, Peiling Zhang, Guiqi Zhu, Biao Wang, Jialiang Cai, Lina Song, Jinglei Wan, Yi Yang, Junxian Du, Yufan Cai, Jian Zhou, Jia Fan, Zhi Dai","doi":"10.1038/s41423-024-01231-0","DOIUrl":"10.1038/s41423-024-01231-0","url":null,"abstract":"Despite the notable efficacy of anti-PD1 therapy in the management of hepatocellular carcinoma (HCC) patients, resistance in most individuals necessitates additional investigation. For this study, we collected tumor tissues from nine HCC patients receiving anti-PD1 monotherapy and conducted RNA sequencing. These findings revealed significant upregulation of GSDME, which is predominantly expressed by tumor-associated macrophages (TAMs), in anti-PD1-resistant patients. Furthermore, patients with elevated levels of GSDME+ macrophages in HCC tissues presented a poorer prognosis. The analysis of single-cell sequencing data and flow cytometry revealed that the suppression of GSDME expression in nontumor cells resulted in a decrease in the proportion of M2-like macrophages within the tumor microenvironment (TIME) of HCC while concurrently augmenting the cytotoxicity of CD8 + T cells. The non-N-terminal fragment of GSDME within macrophages combines with PDPK1, thereby activating the PI3K-AKT pathway and facilitating M2-like polarization. The small-molecule Eliprodil inhibited the increase in PDPK1 phosphorylation mediated by GSDME site 1. The combination of Eliprodil and anti-PD1 was effective in the treatment of both spontaneous HCC in c-Myc + /+;Alb-Cre + /+ mice and in a hydrodynamic tail vein injection model, which provides a promising strategy for novel combined immunotherapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1505-1521"},"PeriodicalIF":21.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575319","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

Specific ECM degradation potentiates the antitumor activity of CAR-T cells in solid tumors 特异性 ECM 降解可增强 CAR-T 细胞在实体瘤中的抗肿瘤活性。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-10-29 DOI: 10.1038/s41423-024-01228-9

Rui Zheng, Kuo Shen, Sixin Liang, Yanhong Lyu, Siyan Zhang, Hao Dong, Yuanfeng Li, Yujie Han, Xiaojuan Zhao, Yiting Zhang, Pengju Wang, Ruotong Meng, Shukun Bai, Jianxun Yang, Guofang Lu, Jia Li, Angang Yang, Rui Zhang, Bo Yan

{"title":"Specific ECM degradation potentiates the antitumor activity of CAR-T cells in solid tumors","authors":"Rui Zheng, Kuo Shen, Sixin Liang, Yanhong Lyu, Siyan Zhang, Hao Dong, Yuanfeng Li, Yujie Han, Xiaojuan Zhao, Yiting Zhang, Pengju Wang, Ruotong Meng, Shukun Bai, Jianxun Yang, Guofang Lu, Jia Li, Angang Yang, Rui Zhang, Bo Yan","doi":"10.1038/s41423-024-01228-9","DOIUrl":"10.1038/s41423-024-01228-9","url":null,"abstract":"Although major progress has been made in the use of chimeric antigen receptor (CAR)-T-cell therapy for hematological malignancies, this method is ineffective against solid tumors largely because of the limited infiltration, activation and proliferation of CAR-T cells. To overcome this issue, we engineered CAR-T cells with synthetic Notch (synNotch) receptors, which induce local tumor-specific secretion of extracellular matrix (ECM)-degrading enzymes at the tumor site. SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors, with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM. In addition, this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors, resulting in tumor regression without toxicity in vivo. Notably, synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids. Thus, we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells, providing a strategy for targeting ECM-rich solid tumors.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1491-1504"},"PeriodicalIF":21.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41423-024-01228-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544062","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}

引用次数: 0

Glut3 promotes cellular O-GlcNAcylation as a distinctive tumor-supportive feature in Treg cells Glut3 促进细胞 O-GlcNAcylation 是 Treg 细胞支持肿瘤的一个独特特征。

IF 21.8 1区医学

Cellular &Molecular Immunology Pub Date : 2024-10-28 DOI: 10.1038/s41423-024-01229-8

Amit Sharma, Garima Sharma, Zhen Gao, Ke Li, Mutong Li, Menglin Wu, Chan Johng Kim, Yingjia Chen, Anupam Gautam, Hong Bae Choi, Jin Kim, Jung-Myun Kwak, Sin Man Lam, Guanghou Shui, Sandip Paul, Yongqiang Feng, Keunsoo Kang, Sin-Hyeog Im, Dipayan Rudra

{"title":"Glut3 promotes cellular O-GlcNAcylation as a distinctive tumor-supportive feature in Treg cells","authors":"Amit Sharma, Garima Sharma, Zhen Gao, Ke Li, Mutong Li, Menglin Wu, Chan Johng Kim, Yingjia Chen, Anupam Gautam, Hong Bae Choi, Jin Kim, Jung-Myun Kwak, Sin Man Lam, Guanghou Shui, Sandip Paul, Yongqiang Feng, Keunsoo Kang, Sin-Hyeog Im, Dipayan Rudra","doi":"10.1038/s41423-024-01229-8","DOIUrl":"10.1038/s41423-024-01229-8","url":null,"abstract":"Regulatory T cells (Tregs) establish dominant immune tolerance but obstruct tumor immune surveillance, warranting context-specific mechanistic insights into the functions of tumor-infiltrating Tregs (TIL-Tregs). We show that enhanced posttranslational O-linked N-acetylglucosamine modification (O-GlcNAcylation) of cellular factors is a molecular feature that promotes a tumor-specific gene expression signature and distinguishes TIL-Tregs from their systemic counterparts. We found that altered glucose utilization through the glucose transporter Glut3 is a major facilitator of this process. Treg-specific deletion of Glut3 abrogates tumor immune tolerance, while steady-state immune homeostasis remains largely unaffected in mice. Furthermore, by employing mouse tumor models and human clinical data, we identified the NF-κB subunit c-Rel as one such factor that, through Glut3-dependent O-GlcNAcylation, functionally orchestrates gene expression in Tregs at tumor sites. Together, these results not only identify immunometabolic alterations and molecular events contributing to fundamental aspects of Treg biology, specifically at tumor sites but also reveal tumor-specific cellular properties that can aid in the development of Treg-targeted cancer immunotherapies.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"21 12","pages":"1474-1490"},"PeriodicalIF":21.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521118","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