Cellular expression and regulation of interleukin-27 in the neonatal immune syste

描述(申请人提供)：微生物感染是全球婴儿死亡的主要原因，这是该人群免疫防御受损的结果。我们发现，与健康的成人巨噬细胞相比，人脐血来源的巨噬细胞表达IL-27的水平更高。我们进一步确定，在小鼠模型中，新生儿IL-27的升高在整个婴儿期都保持不变。IL-27是IL-12家族中的一种异二聚体细胞因子，主要由抗原提呈细胞产生，对多种免疫细胞类型具有免疫抑制作用。因此，在生命早期，IL-27表达的升高可能导致了这一人群所描述的免疫反应的某些缺陷。这项建议的本质是了解导致新生儿和婴儿IL-27产生增加的完整细胞类型，以及进一步了解导致差异表达的分子机制。在第一个目标中，我们将评估产生IL-27的细胞的细胞表型，特别是髓系来源的抑制细胞。这些细胞具有很强的抑制炎症和适应性免疫的能力。第二个目的是检验IL-27受表观遗传机制调控的假说，表观遗传机制有助于年龄相关表达的差异。这将集中在DNA甲基化和通过组蛋白修饰的核小体重塑。我们提出了一项研究，调查IL-27对新生儿免疫反应的影响。减少新生儿和婴儿IL-27表达的方法可能会改善疫苗接种反应，降低对感染性物质的易感性。

DESCRIPTION (provided by applicant): Microbial infections are a major cause of infant mortality worldwide as a result of impaired immune defenses in this population. We have found that human umbilical cord blood-derived macrophages express interleukin (IL) - 27 at an elevated level as compared with healthy adult macrophages. We have further determined that elevated IL-27 production by newborns is maintained through infancy in a mouse model. IL-27 is a heterodimeric cytokine of the IL-12 family that is produced primarily by antigen presenting cells and is immunosuppressive toward a variety of immune cell types. Thus, elevated IL-27 expression early in life may contribute to some of the deficiencies described with immune responses by this population. The nature of this proposal is to understand the complete repertoire of cell types that contribute to elevated IL-27 production in neonates and infants as well as to further understand the molecular mechanisms responsible for differential expression. In the first aim, we will evaluate the cellular phenotypes of cells that produce IL-27 with a particular focus toward myeloid-derived suppressor cells. These cells have potent ability to suppressive inflammation and adaptive immunity. The second aim tests the hypothesis that IL-27 is regulated by epigenetic mechanisms that contribute to differences in age-related expression. This will focus on DNA methylation and nucleosome remodeling through histone modification. We have proposed research that investigates the impact of IL-27 on neonatal immune responses. Approaches to reduce expression of IL-27 in newborns and infants may improve vaccination responses and reduce susceptibility to infectious agents.