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
{"title":"Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities","authors":"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","doi":"10.1126/sciimmunol.adh0368","DOIUrl":null,"url":null,"abstract":"<div >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 <i>Gfpt1</i> are critical for T cell expansion and function. Further, T helper (T<sub>H</sub>1) cells synthesized uridine diphosphate <i>N</i>-acetylglucosamine more rapidly and were more impaired by <i>Gfpt1</i> deficiency than T<sub>H</sub>17 cells. Screening IEI genes found that <i>Bcl11b</i> promotes the CD4 T cell mitochondrial activity and <i>Mcl1</i> 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.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6000,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/sciimmunol.adh0368","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
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.
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.