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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.

项目总结/摘要病毒感染的结果存在性别偏见，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的二型性，免疫细胞组成和功能。因此，令人惊讶的是，自然杀伤（NK）细胞的数量，第一个与女性相比，男性的HCMV防御线增加。这里我们展示了小鼠模型和人类样本，虽然男性拥有增加的NK细胞数量，他们产生较少的IFN-γ，一个关键的亲，用于NK介导的抗病毒应答的炎性细胞因子。这种差异并不是因为性腺激素，因为这些差异仍然存在于性腺切除小鼠。相反，X屏幕在NK细胞中逃避失活并显示性二态表达的染色体基因鉴定了UTX，一种通过染色质重组改变转录程序的表观遗传调节因子。 NK细胞特异性UTX缺失表型复制了男性NK细胞的多种特征，包括NK细胞的增加。减少IFN-γ的产生。因此，我们假设NK细胞的性别差异可以归因于 X连锁UTX的差异表达，其在NK细胞适应性中重要的位点重组染色质，功能在目标1中，我们将定义UTX介导的NK细胞数量的时间控制，并确定是否细胞适应性的差异是男性与女性相比NK细胞稳态差异的基础。在Aim中 2、探讨UTX在促进NK细胞杀伤活性中的作用，以及降低男性NK细胞中UTX水平是否会影响NK细胞的杀伤活性。细胞也损害其细胞毒性能力。在目标3中，我们将描述UTX 控制对NK细胞稳态和功能重要的基因座处的染色质可及性和基因表达。从这些研究中获得的知识将有助于我们对性别差异的基本理解抗病毒反应和NK细胞。更深入地了解性别差异将有利于人类的整体健康通过揭示免疫治疗的新靶点和指导优化抗病毒免疫的干预措施。