Sex Differences in NK Cells Mediated by X-linked UTX

X连锁UTX介导的NK细胞性别差异

基本信息

批准号：
10750843
负责人：
Timothy E O'Sullivan
金额：
$ 65.23万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-07 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750843
关键词：
Ablation Antiviral Response Apoptosis Apoptotic BCL2 gene Binding Biological Assay CRISPR/Cas technology Cell Count Cell Maturation Cell physiology Cell-Mediated Cytolysis Cells Chromatin Chromatin Remodeling Factor Cytomegalovirus Cytomegalovirus Infections Data Development Disease Disparity EP300 gene Effector Cell Epigenetic Process Female Gene Expression Genes Genetic Transcription Genomics Gonadal Hormones Granzyme Health Homeostasis Hormones Human Immune Immune response Immunotherapy Impairment In Vitro Inflammatory Interferon Type II Intervention Knowledge Link Lymphocyte Mammals Mediating Methyltransferase Molecular Murid herpesvirus 1 Mus Natural Killer Cells Outcome Phenocopy Positioning Attribute Predisposition Production Regulation Resistance Role Sampling Sex Bias Sex Chromosomes Sex Differences System Testing Viral Viral Cancer Virus Diseases X Chromosome X Inactivation antiviral immunity cell type cytokine cytotoxic cytotoxicity differential expression epigenomic profiling fitness genomic locus histone demethylase improved outcome in vivo insight male mouse model new therapeutic target p300/CBP-Associated Factor perforin personalized therapeutic programs recruit response sex sexual dimorphism

项目摘要

PROJECT SUMMARY/ABSTRACT Viral infection outcomes are sex-biased, with males generally more susceptible to human cytomegalovirus (HCMV) and other viral infections compared to females. These differences may reflect sexual dimorphism in immune cell composition and function. As such, it is surprising that numbers of natural killer (NK) cells, a first line of defense against HCMV, are increased in males compared to females. Here we show in mouse models and human samples that while males harbor increased NK cell numbers, they produce less IFN-γ, a critical pro- inflammatory cytokine for NK-mediated anti-viral responses. This difference is not due to divergent levels of gonadal hormones, since these differences are still present in gonadectomized mice. Instead, a screen for X chromosome genes that escape inactivation and demonstrate sexually dimorphic expression in NK cells identified UTX, an epigenetic regulator that alters transcriptional programs through reorganization of chromatin. NK cell-specific UTX deletion phenocopies multiple features of male NK cells, which include increased NK numbers and reduced IFN-γ production. Thus, we hypothesize that NK cell sex differences can be attributed to differential expression of X-linked UTX, which reorganizes chromatin at loci important in NK cell fitness and function. In Aim 1, we will define UTX-mediated temporal control of NK cell numbers and determine whether differences in cellular fitness underlie differences in NK cell homeostasis in males compared to females. In Aim 2, we will delineate UTX’s role in promoting NK cell cytotoxic activity and whether lower UTX levels in male NK cells also impairs their cytotoxic capacity. In Aim 3, we will delineate molecular mechanisms by which UTX controls chromatin accessibility and gene expression at loci important for NK cell homeostasis and function. Knowledge gained from completion of these studies will contribute to our basic understanding of sex differences in anti-viral responses and NK cells. A deeper understanding of sex differences will benefit human health overall by revealing new targets for immunotherapy and guiding interventions for optimizing anti-viral immunity.

项目概要/摘要病毒感染结果存在性别偏见，男性通常更容易感染人类巨细胞病毒 (HCMV) 和其他病毒感染与女性相比，这些差异可能反映了性别二态性。因此，自然杀伤 (NK) 细胞的数量首次令人惊讶。与雌性小鼠相比，雄性小鼠的 HCMV 防御线有所增强。和人类样本中，虽然男性体内的 NK 细胞数量有所增加，但它们产生的 IFN-γ 却较少，而 IFN-γ 是一种关键的促 NK 介导的抗病毒反应的炎症细胞因子的差异并不是由于 NK 介导的抗病毒反应的水平不同所致。性腺激素，因为这些差异仍然存在于性腺切除的小鼠中，而是进行 X 筛查。逃避失活并在 NK 细胞中表现出性别二态性表达的染色体基因确定了 UTX，一种表观遗传调节因子，可通过染色质重组来改变转录程序。 NK 细胞特异性 UTX 缺失表现出男性 NK 细胞的多种特征，其中包括 NK 增加因此，我们发现 NK 细胞性别差异可归因于。 X 连锁 UTX 的差异表达，可在对 NK 细胞适应性重要的位点重组染色质，在目标 1 中，我们将定义 UTX 介导的 NK 细胞数量的时间控制，并确定是否存在。 In Aim 指出，细胞适应性的差异是男性与女性 NK 细胞稳态差异的基础。 2、我们将阐述UTX在促进NK细胞细胞毒活性中的作用以及是否降低男性NK中的UTX水平在目标 3 中，我们将描述 UTX 的分子机制。控制对 NK 细胞稳态和功能重要的位点的染色质可及性和基因表达。完成这些研究获得的知识将有助于我们对性别差异的基本理解更深入地了解性别差异将有益于人类整体健康。通过揭示免疫治疗的新靶点并指导优化抗病毒免疫的干预措施。