Regulation of murine neonatal Th2 function

描述（由申请人提供）：小鼠生命早期的辅助性T细胞应答，特别是人类婴儿的过敏原特异性应答偏向于Th2功能。这种早期Th2优势与Th2介导的疾病如过敏和哮喘的发展有关。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活性。然而，目前缺乏的是对生命早期Th2功能基础的透彻理解。这些信息对于制定有效的策略以靶向Th2介导的儿科疾病至关重要。为此，本提案的长期目标是确定新生儿Th2应答的分子和细胞调节。具体目标1将侧重于新生儿Th2功能的分子事件。我们已经产生了令人信服的证据表明，新生儿Th2的偏见，至少在部分，在表观遗传水平的调节。与成人CD4+细胞不同，幼稚新生儿CD4+细胞显示Th2基因座中关键调控区的去甲基化。因此，我们将进一步研究这一现象，其特异性和其发育起源，并测试的想法，DMA甲基化是至关重要的定义Th2效应分化和功能的发展差异。具体目标2和3将检查新生儿中富集的细胞成分，这些细胞成分是Th2活性的主要来源。首先，由于许多新生儿CD4+细胞可能是胎儿前体细胞的直接后代，特异性目标2将测试新生儿Th2细胞是胎儿起源的想法。支持这一假设来自我们的观察，外周血CD4+细胞来源于胎儿胸腺细胞具有增强的Th2功能。第二，外周血CD4+细胞在新生儿中的比例比在成人外周血中的比例更高。因此，具体目标3将阐明RTE是新生儿Th2功能来源的假设。我们的研究结果支持这一观点，即新生儿外周血CD4+细胞的功能与成人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.