T cell immunity to CMV in utero and in early childhood

子宫内和幼儿期 T 细胞对 CMV 的免疫

• 批准号: 10576950
• 负责人: MARGARET E FEENEY
• 金额: $ 77.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-18 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576950
• 关键词: Adult; Antigens; Antiviral Response; Biological Assay; Birth; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cellular Immunity; Child; Childhood; Chronic; Clinical; Clinical Data; Containment; Coupled; Critical Pathways; Cytomegalovirus; Cytomegalovirus Infections; Cytometry; Data; Development; Effector Cell; Epigenetic Process; Exhibits; Fetal Development; Fetus; Genetic Transcription; Granzyme; Growth; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Impairment; Individual; Infant; Infection; Life; Measures; Mediating; Memory; Microcephaly; Modeling; Molecular; Mothers; Neonatal; Neurologic; Outcome; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Play; Population; Pregnancy; Primary Infection; Process; Resolution; Role; Sampling; Symptoms; System; T cell receptor repertoire sequencing; T cell response; T-Cell Development; T-Lymphocyte; Testing; Thymus Gland; Time; Toddler; Umbilical Cord Blood; Viral; Viral Load result; Viral Physiology; Viremia; Virus Diseases; Virus Replication; Virus Shedding; age related; arm; chronic infection; cohort; congenital cytomegalovirus; congenital infection; cytotoxic CD8 T cells; deafness; differential expression; early childhood; fetal; fetal programming; high dimensionality; in utero; infancy; infant infection; innovation; insight; inter-individual variation; mouse model; multimodality; neonatal infection; neonatal mice; neonate; pathogen; postnatal; precursor cell; programs; prospective; response; stem; stem-like cell; transcriptomics

Abstract: CMV infection in utero leads to prolonged viremia and often devastating clinical sequelae. In adults, it is established that the T cell response to CMV is required for containment of viremia. However, the immunologic determinants of viral control and clinical sequelae following congenital CMV infection are not known. In this project, we will study the immune response to CMV as a window into immune ontogeny and the age-related maturation of antiviral T cell function. We will leverage a large cohort of mother-infant pairs with samples banked longitudinally for immunologic studies. This cohort, which includes a large number of infants infected with CMV in utero and others infected during early childhood, affords a unique opportunity to examine the relationship between the age-related maturation of the immune system and control of CMV viremia. Prior studies have shown that two populations of cytotoxic T lymphocytes, CD8 T and gd T cells, expand and differentiate upon CMV infection in utero. We hypothesize that T cells generated during fetal development (including both CD8 and gd T cells) are intrinsically biased toward rapid differentiation into terminal effector cells. We further hypothesize that this effector-biased programming limits the ability of infant CD8 T cells to generate the long-lived memory sub-populations that are required for sustained control of a chronic viral infection. This hypothesis is supported by data from experimental murine models but has not been fully examined in human infants in the context of a natural pathogen. While the CD8 response continues to mature postnatally, gd T cells develop earlier in gestation and exhibit many innate-like qualities that could enable them to act as important antiviral effectors in utero. Remarkably, gd T cells that express CMV-reactive gd TCRs and pre-programmed effector functions are already present in the fetal thymus at mid-gestation. These fetal gd T cells can be rapidly activated to produce IFNg and granzymes upon stimulation. Hence, we hypothesize that fetal gd T cells play an important role in mediating anti-CMV effector functions in utero, while the adaptive ab T cell response matures. In the first two aims, we will compare gd and CD8 T cell responses in congenitally CMV- infected newborns to those of children who acquire primary CMV infection during the second year of life, in order to identify critical pathways of immune maturation. CD8 and gd T cells will be assessed by high- parameter cytometry, functional assays, and paired transcriptional and TCRseq profiling of individual cells in order to identify differences in the response to CMV based on the developmental window during which infection occurred. In Aim 3, we will relate these immunologic parameters to clinical sequelae and the resolution of viremia during infancy in order to identify immune correlates of viral containment. Understanding how variability in the infant immune response to CMV relates to clinical and virologic outcomes, and how age- related differences in this immune response enable the gradual resolution of viremia postnatally, could lend great insight into antiviral T cell function in early life.

抽象的： 子宫内的CMV感染会导致病毒血症延长，并且经常毁灭性临床后遗症。在成年人中是 确定T细胞对CMV的反应是遏制病毒血症所必需的。但是，免疫学 先天性CMV感染后病毒控制和临床后遗症的决定因素尚不清楚。在这个 项目，我们将研究对CMV的免疫反应，以作为免疫本体发育和年龄相关的窗口 抗病毒T细胞功能的成熟。我们将利用大量的母亲对样品对 纵向进行免疫学研究。这个队列，其中包括大量的婴儿 在子宫内CMV和其他童年时期感染的其他人，为检查该公司提供了独特的机会 免疫系统与年龄相关的成熟与CMV病毒血症的控制之间的关系。事先的 研究表明，两个细胞毒性T淋巴细胞CD8和GD T细胞的群体扩展和 区分子宫内CMV感染。我们假设在胎儿发育过程中产生的T细胞 （包括CD8和GD T细胞）本质上偏向于快速分化为终端效应器 细胞。我们进一步假设这种效应偏置的编程限制了婴儿CD8 T细胞的能力 生成持续控制慢性病毒所需的长期记忆子群 感染。实验鼠模型的数据支持了这一假设，但尚未完全 在天然病原体的背景下在人类婴儿中检查。虽然CD8响应继续成熟 在产后，GD T细胞在妊娠中早期发展，并表现出许多天生的品质，可以使它们能够 充当子宫内重要的抗病毒效应子。值得注意的是，表达CMV反应性GD TCR的GD T细胞和 妊娠中期，胎儿胸腺中已经存在预编程的效应子功能。这些胎儿GD T 细胞可以在刺激后迅速激活以产生IFNG和颗粒状。因此，我们假设 胎儿GD T细胞在介导抗CMV效应子功能中起重要作用，而自适应AB T 细胞反应成熟。在前两个目标中，我们将比较先天CMV-中的GD和CD8 T细胞反应。 在生命的第二年，将新生儿感染了新生儿， 为了识别免疫成熟的关键途径。 CD8和GD T细胞将通过高 - 参数细胞仪，功能测定以及单个细胞中各个单元格的成对转录和TCRSEQ分析 为了根据发展窗口确定对CMV的响应的差异 发生感染。在AIM 3中，我们将将这些免疫学参数与临床后遗症和 在婴儿期分辨出病毒血症，以鉴定病毒遏制的免疫相关性。理解 婴儿免疫反应对CMV的可变性与临床和病毒学结局以及年龄如何关系 这种免疫反应中的相关差异可以在产后逐步解决病毒血症，可以借出 对早期生命中抗病毒T细胞功能的深入了解。