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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

基本信息

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
项目类别：
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

项目摘要

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.

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