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

描述(申请人提供)：婴儿对疫苗的抗体反应比年龄较大的儿童低，包括对T依赖的新抗原的抗体反应，这一反应需要抗原未成熟的CD4T细胞和B细胞激活并分化为 T滤泡辅助细胞(TFH)和抗体分泌浆细胞。我们假设，婴儿疫苗免疫原性受损的部分原因是天然淋巴细胞的内在机制，包括：1)在婴儿期新产生的过渡型CD4T细胞和B细胞具有降低的效应功能；2)新生儿和婴儿中存在天然淋巴细胞，它们保留了胎儿成熟停滞和/或造血干细胞(HSC)来源的耐受程序。为了验证这些假说，将开发一套与获得转铁蛋白和B细胞效应功能有关的细胞学特征(目标1)和分子特征[信使核糖核酸表达和DNA甲基化(目标2)]，以有力地区分新生儿和成人的天然淋巴细胞。我们预计，这种新生儿的特征将与未成熟的CD4T细胞和B细胞系前体细胞(即分别反映成熟停滞状态的骨髓中的CD4+CD8胸腺细胞和未成熟B细胞)共享，并与胎儿CD4T细胞和B细胞共享，反映持续的胎儿HSC分化计划。我们预计，胎儿HSC程序的成熟停滞和出生后保留都会导致婴儿免疫功能下降。目的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正常与营养不良相关的幼稚淋巴细胞出生后成熟扰动之间的关系。我们假设胎儿营养不良将在表观遗传学上重新编程适应性免疫系统，以应对过早的免疫衰老和疫苗免疫原性受损。这一点将通过确定疫苗免疫原性与出生前有或没有经历过营养应激的婴儿的NA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，这些研究将极大地增强我们对幼稚的CD4T细胞和B细胞的出生后成熟的正常过程，它们对疫苗免疫原性的影响，以及它们受到产前营养应激的干扰的理解。他们还可能指出通过早期营养干预或通过治疗性扩大天然淋巴细胞室来增强婴儿免疫反应的方法。

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.