Transitional and Naive CD4 T cells and B cells in Infant Vaccine Responses

婴儿疫苗反应中的过渡型和初始 CD4 T 细胞和 B 细胞

• 批准号: 8299284
• 负责人: DAVID BRAM LEWIS
• 金额: $ 38.74万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-03 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299284
• 关键词: Adult; African; Age; Alloantigen; Antibodies; Antibody Formation; Antigens; Apoptosis; B-Cell Development; B-Lymphocytes; Birth; Blood Cells; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell physiology; Cells; Characteristics; Child; Country; Cytometry; DNA Methylation; Developing Countries; Development; Dietary Intervention; Drug usage; Effector Cell; Emigrant; Epigenetic Process; Fetal Malnutrition; First Pregnancy Trimester; Frequencies; Gambia; Gene Expression; Helper-Inducer T-Lymphocyte; Hematopoietic stem cells; Homeostasis; Immune; Immune response; Immune system; Immunity; Impairment; Inactivated Vaccines; Infant; Infection; Life; Lymphocyte; Malnutrition; Mature B-Lymphocyte; Memory; Messenger RNA; Methylation; Molecular; Molecular Profiling; Neonatal; Nutritional; Peripheral; Phenotype; Plasma Cells; Play; Polysaccharides; Predictive Value; Pregnancy; Process; Production; Property; Proteins; RNA; Research; Risk; Role; Stress; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Transitional Cell; Vaccine Antigen; Vaccines; Work; adaptive immunity; age related; cell type; cytokine; dietary supplements; early childhood; experience; fetal; fetal programming; fetus cell; genome-wide; immune function; immunogenicity; improved; infancy; mRNA Expression; neonate; precursor cell; premature; prenatal; programs; response; senescence; stem cell differentiation; thymocyte; vaccine-induced immunity

DESCRIPTION (provided by applicant): The antibody response of infants to vaccines is reduced compared to that of older children, including for T- dependent neoantigens, a response that requires the activation and differentiation of antigenically-naiveCD4 T cells and B cells into T follicular helper cells (TFh) and antibody-secreting plasma cells, respectively. We hypothesize that impaired infant vaccine immunogenicity is due, in part, to na¿ve lymphocyte intrinsic mechanisms that include: 1) the predominance during infancy of newly-produced transitional-type CD4 T cells and B cells that have a reduced capacity for effector function; 2) the presence in neonates and infants of na¿ve lymphocytes that retain a fetal program of maturational arrest and/or hematopoietic stem cell (HSC)-derived tolerance. To test these hypotheses, a set of cytometric features (Aim 1) and molecular features [mRNA expression and DNA methylation (Aim 2)] involved in the acquisition of TFh and B-cell effector function will be developed that robustly distinguishes neonatal na¿ve lymphocytes from their adult counterparts. We expect that this neonatal signature will be shared with immature CD4 T-lineage and B-lineage precursor cells (i.e., CD4+CD8- thymocytes and immature B cells of the bone marrow, respectively), reflecting a state of maturational arrest, and with fetal CD4 T cells and B cells, reflecting a persistent fetal HSC differentiation program. We expect that both maturational arrest and the post-natal retention of a fetal HSC program will contribute to reduced immune function in the infant. Aim 3 will longitudinally study a group of infants and young children from The Gambia to determine the relationship between vaccine immunogenicity and normal vs. malnutrition-related perturbation of the post-natal maturation of na¿ve lymphocytes. We hypothesize that fetal malnutrition will epigenetically reprogram the adaptive immune system for premature immune senescence and impaired vaccine immunogenicity. This will be tested by determining the relationship of vaccine immunogenicity with na¿ve lymphocyte phenotype/function, mRNA expression, DNA methylation, and cell homeostasis in infants who have or have not experienced pre-natal nutritional stress. Together, these studies will substantially enhance our understanding of the normal process of post-natal maturation of the naiveCD4 T-cell and B-cell compartments, their influence on vaccine immunogenicity, and their perturbation by prenatal nutritional stress. They may also point out approaches by which infant immune responses could be enhanced by nutritional intervention in early life or by therapeutic expansion of the na¿ve lymphocyte compartment. PUBLIC HEALTH RELEVANCE: The infant does not respond to vaccines as well as older children and adults, and, as a consequence, is more vulnerable to infections. This research will determine why two types of blood cells that work together to make a vaccine response - the CD4 T cell and the B cell - are not as effective in the infant as in older children and adults. The importance of malnutrition during pregnancy on the infant's CD4 T-cell and B-cell function and the vaccine response will also be studied in a group of infants from The Gambia, a less developed African country. This research will determine ways in which the infant vaccine response could be improved by nutritional supplements early in life or by using drugs that boost the function of CD4 T cells or B cells.

描述（由申请人提供）：与年龄较大的儿童相比，婴儿对疫苗的抗体应答降低，包括T依赖性新抗原，这种应答需要抗原初始的CD 4 T细胞和B细胞活化和分化为T细胞。 T滤泡辅助细胞（TFh）和抗体分泌浆细胞，分别。我们假设，婴儿疫苗免疫原性受损部分是由于幼稚淋巴细胞的内在机制，包括：1）婴儿期新产生的过渡型CD 4 T细胞和B细胞的优势，这些细胞具有降低的效应功能; 2）新生儿和婴儿中存在幼稚T细胞，保持成熟停滞和/或造血干细胞（HSC）衍生的耐受性的胎儿程序。为了检验这些假设，将开发一组涉及TFh和B细胞效应器功能获得的细胞计数特征（目标1）和分子特征[mRNA表达和DNA甲基化（目标2）]，其将新生儿幼稚淋巴细胞与其成人对应物强有力地区分开来。我们预期这种新生儿特征将与未成熟的CD 4 T谱系和B谱系前体细胞共享（即，CD 4 + CD 8-胸腺细胞和骨髓的未成熟B细胞），反映了成熟停滞的状态，以及胎儿CD 4 T细胞和B细胞，反映了持续的胎儿HSC分化程序。我们预计，胎儿HSC程序的成熟停滞和产后保留将有助于降低婴儿的免疫功能。目标3将对冈比亚的一组婴幼儿进行纵向研究，以确定疫苗免疫原性与幼稚淋巴细胞出生后成熟的正常与营养不良相关扰动之间的关系。我们假设胎儿营养不良将表观遗传学重新编程适应性免疫系统过早免疫衰老和受损的疫苗免疫原性。这将通过确定有或没有经历过产前营养应激的婴儿中疫苗免疫原性与幼稚淋巴细胞表型/功能、mRNA表达、DNA甲基化和细胞稳态的关系来进行测试。总之，这些研究将大大提高我们对出生后幼稚CD 4 T细胞和B细胞室成熟的正常过程，它们对疫苗免疫原性的影响，以及它们受产前营养应激的干扰的理解。他们还可能指出，通过在生命早期进行营养干预或通过治疗性扩大幼稚淋巴细胞区室，可以增强婴儿免疫反应的方法。 公共卫生关系：婴儿对疫苗的反应不如年龄较大的儿童和成人，因此更容易受到感染。这项研究将确定为什么两种类型的血细胞一起工作，使疫苗反应-CD 4 T细胞和B细胞-是不一样的有效性，在婴儿中，作为在年龄较大的儿童和成人。的 此外，还将在来自非洲欠发达国家冈比亚的一组婴儿中研究妊娠期间营养不良对婴儿CD 4 T细胞和B细胞功能以及疫苗反应的重要性。这项研究将确定如何通过在生命早期补充营养或使用增强CD 4 T细胞或B细胞功能的药物来改善婴儿疫苗反应。