Induction of effector lymphocyte lethargy by helminth coinfection

蠕虫共感染诱导效应淋巴细胞昏睡

• 批准号: 9403748
• 负责人: William Clark Gause
• 金额: $ 58.7万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-19 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403748
• 关键词: Affect; Antigen Receptors; Antigens; Autoimmune Process; Biogenesis; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell physiology; Cells; Cytokine Receptors; Data; Defect; Depressed mood; Development; Disease; Disease Progression; Down-Regulation; Effector Cell; Environment; Exhibits; Functional disorder; Genomic approach; Helminths; Human; IL4 gene; Immune response; Immunity; Immunology; Immunotherapy; Infection; Inflammatory; Interleukin-10; Interleukin-4; Investigation; Journals; Lethargies; Lymphocyte; Mediating; Metabolism; Mitochondria; Modeling; Mus; Phenotype; Population; Publishing; Receptor Signaling; Role; Signal Transduction; T cell response; T-Lymphocyte; Testing; Therapeutic; Toxoplasma gondii; Up-Regulation; Vaccination; biomarker identification; co-infection; cytokine; follow-up; immunoregulation; insight; mitochondrial dysfunction; mitochondrial metabolism; mouse model; novel; pathogen; programs; response; vaccine efficacy

Abstract: Helminth infections occur in populations worldwide and potentially modulate the immune response to unrelated pathogens. An important consideration in the field is that concomitant helminth infection could decrease the efficacy of vaccines. It is not known how helminth infection impacts the formation and function of effector cells. Using an ecologically appropriate model of mouse coinfection with H. polygyrus and vaccination with T. gondii, we find that helminth infection inhibited the differentiation of effector CD8 T cells. Furthermore, the effector CTLs that develop in coinfected mice exhibit an “lethargic” phenotype, marked by a deficiency in Tfb1m and depressed mitochondrial biogenesis and defective effector cytokine response. Defective CD8 T cell differentiation was associated also associated with an upregulation of Spry2, a negative regulator of receptor signaling. Induction of defective effector differentiation by helminth coinfection was mediated by host IL-4 and IL-10. To advance mechanistic understanding of helminth induced effector lymphocyte lethargy, we propose three specific aims. In Aim 1, we will leverage our recently developed technical advances and insights to delineate how helminth coinfection negatively impacts CD8 T cell activation, proliferation and differentiation. In Aim2, we will interrogate the functional role of mitochondrial insufficiency in helminth-induced effector dysfunction. Finally, in Aim 3, we will dissect the role of Spry2 and CD8 T cell intrinsic IL4 and IL-10 signaling in helminth-induced lymphocyte lethargy. Together, these studies will advance mechanistic understanding of effector cell dysfunction and provide avenues for therapeutic reversal. !

摘要： 蠕虫感染发生在世界各地的人群中，并可能调节免疫系统。 对不相关病原体的反应。该领域的一个重要考虑因素是， 伴随的蠕虫感染可降低疫苗的效力。目前还不知道 蠕虫感染如何影响效应细胞的形成和功能。使用 生态学上合适的小鼠与H.多脑回与疫苗接种 和T.弓形虫感染抑制了效应细胞CD 8的分化， T细胞。此外，在共感染的小鼠中产生的效应CTL表现出一种免疫抑制作用。 “昏睡”表型，以Tfb 1 m缺陷和线粒体抑制为标志 生物发生和有缺陷的效应细胞因子应答。CD 8 T细胞分化缺陷 也与Spry 2的上调有关，Spry 2是一种负调节因子， 受体信号蠕虫共感染诱导效应子分化缺陷 由宿主IL-4和IL-10介导。推进对蠕虫的机械理解 诱导效应淋巴细胞嗜睡，我们提出了三个具体的目标。在目标1中，我们 利用我们最近开发的技术进步和见解， 蠕虫共感染对CD 8 T细胞活化、增殖和 分化在Aim 2中，我们将询问线粒体功能不足的功能作用， 蠕虫引起的效应器功能障碍最后，在目标3中，我们将剖析Spry 2的作用 和CD 8 T细胞内在的IL-4和IL-10信号在蠕虫诱导的淋巴细胞嗜睡。 总之，这些研究将促进效应细胞的机制理解， 功能障碍，并提供治疗逆转的途径。 !