Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities

IF 17.6 1区 医学 Q1 IMMUNOLOGY
Andrew R. Patterson, Gabriel A. Needle, Ayaka Sugiura, Erin Q. Jennings, Channing Chi, KayLee K. Steiner, Emilie L. Fisher, Gabriella L. Robertson, Caroline Bodnya, Janet G. Markle, Ryan D. Sheldon, Russell G. Jones, Vivian Gama, Jeffrey C. Rathmell
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引用次数: 0

Abstract

Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable previously unappreciated crossover. Analysis of IEMs showed that N-linked glycosylation and the hexosamine pathway enzyme Gfpt1 are critical for T cell expansion and function. Further, T helper (TH1) cells synthesized uridine diphosphate N-acetylglucosamine more rapidly and were more impaired by Gfpt1 deficiency than TH17 cells. Screening IEI genes found that Bcl11b promotes the CD4 T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. Thus, a high degree of functional overlap exists between IEM and IEI genes, and immunometabolic mechanisms may underlie a previously underappreciated intersection of these disorders.
先天性免疫错误和代谢基因的功能重叠决定了 T 细胞代谢的脆弱性
先天性代谢错误(IEMs)和免疫(IEIs)是孟德尔疾病,其复杂的表型和患者的罕见性限制了临床了解。虽然很少有基因被注释为对 IEMs 和 IEIs 都有影响,但免疫代谢需求表明它们在功能上有更大的重叠。在这里,CRISPR 筛选测试了 IEM 基因的免疫学作用和 IEI 基因的代谢作用,发现了大量以前未曾注意到的交叉。对 IEM 的分析表明,N-连接的糖基化和六聚糖途径酶 Gfpt1 对 T 细胞的扩增和功能至关重要。此外,与 T H 17 细胞相比,T 辅助细胞(T H 1)合成尿苷二磷酸 N - 乙酰葡糖胺的速度更快,而且 Gfpt1 缺乏对其损害更大。对 IEI 基因的筛选发现,Bcl11b 可促进 CD4 T 细胞线粒体活性和 Mcl1 的表达,这是防止代谢压力所必需的。因此,IEM 和 IEI 基因之间存在着高度的功能重叠,免疫代谢机制可能是以前未被重视的这些疾病交叉的基础。
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来源期刊
Science Immunology
Science Immunology Immunology and Microbiology-Immunology
CiteScore
32.90
自引率
2.00%
发文量
183
期刊介绍: Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.
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