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

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。我们预计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（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。

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.