Regulation of murine neonatal Th2 function

描述(由申请人提供)：小鼠早期的T辅助反应，特别是人类婴儿的过敏原特异性反应偏向于Th2功能。这种早期的Th2优势与Th2介导的疾病的发展有关，如过敏和哮喘。随着Th2介导的疾病的增加，显然需要开发新的方法来预防和治疗病理性Th2活动。然而，目前缺乏的是对早期生命Th2功能的基础的透彻了解。这些信息对于制定针对Th2介导的儿科疾病的有效策略至关重要。为此，这项提议的长期目标是确定新生儿Th2反应的分子和细胞调控。具体目标1将侧重于控制新生儿Th2功能的分子事件。我们已经产生了令人信服的证据，证明新生儿Th2偏向至少部分是在表观遗传水平上受到调控的。幼稚的新生儿CD4+细胞不同于成年的CD4+细胞，表现出Th2基因位点关键调节区的去甲基化。因此，我们将进一步研究这一现象、其特异性及其发育起源，并检验DMA甲基化对于确定Th2效应器分化和功能的发育差异至关重要的观点。特定目标2和3将检查新生儿中富含的细胞成分，这些成分是Th2活性的主要来源。首先，由于许多新生儿的CD4+细胞可能是胎儿前体细胞的直系后代，因此特定目标2将测试新生儿Th2细胞来自胎儿的想法。对这一假设的支持来自我们的观察，即来自胎儿胸腺细胞的外周CD4+细胞增强了Th2功能。其次，新生儿外周血中的CD4+细胞比成人外周血中含有更多的新近的胸腺移行者(RTE)。因此，特定目标3将解决RTE是新生儿Th2功能来源的假设。这一观点得到了我们发现的支持，即新生儿外周血中的CD4+细胞的功能与成人的RTE相似。

DESCRIPTION (provided by applicant): T helper responses in early life in the mouse and, notably, allergen-specific responses in human infants are biased to Th2 function. This early life Th2 dominance is associated with the development of Th2- mediated diseases, such as allergy and asthma. With Th2-mediated diseases on the rise, there is a clear need for the development of new approaches to prevent and treat pathological Th2 activity. However, what is currently lacking is a thorough understanding of the basis of early life Th2 function. This information is critical for formulating effective strategies to target Th2-mediated pediatric disease. To this end, the long term goals of this proposal are to determine the molecular and cellular regulation of neonatal Th2 responses. Specific Aim 1 will focus on the molecular events governing neonatal Th2 function. We have generated compelling evidence that the neonatal Th2 bias is regulated, at least in part, at the epigenetic level. Naive neonatal CD4+ cells, unlike adult CD4+cells, show demethylation of a key regulatory region in the Th2 locus. Thus, we will further investigate this phenomenon, its specificity and its developmental origin, and test the idea that DMA methylation is critical for defining developmental differences in Th2 effector differentiation and function. Specific Aims 2 and 3 will examine cellular components enriched in neonates that are strong candidates for being the major sources of Th2 activity. First, since many neonatal CD4+ cells are likely to be direct descendants of fetal precursors, Specific Aim 2 will test the idea that neonatal Th2 cells are of fetal origin. Support for this hypothesis comes from our observation that peripheral CD4+ cells derived from fetal thymocytes have enhanced Th2 function. Second, the peripheral CD4+ population in neonates contains proportionally many more recent thymic emigrants (RTE) than found in peripheral populations in adults. Therefore, Specific Aim 3 will address the hypothesis that RTE are the source of Th2 function in neonates. This idea is supported by our findings that the function of peripheral CD4+ cells in neonates resembles that of RTE in adults.