Regulation of murine neonatal Th2 function

小鼠生命早期的辅助性T细胞反应，特别是人类婴儿的过敏原特异性反应 偏向于Th2功能。这种早期生命Th2优势与Th2的发育相关， 介导的疾病，如过敏和哮喘。随着Th2介导的疾病的增加， 需要开发新的方法来预防和治疗病理性Th2活性。不过 目前缺乏的是对生命早期Th2功能基础的透彻理解。该信息 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，长 该建议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将集中在控制新生儿Th2功能的分子事件。我们已经生成 令人信服的证据表明，新生儿的Th2偏好，至少部分，在表观遗传水平的调节。天真 与成人CD4+细胞不同，新生儿CD4+细胞显示出Th2基因座中关键调节区的去甲基化。 因此，我们将进一步研究这一现象，其特异性和发展的起源，并测试 DMA甲基化对于定义Th2效应分化中的发育差异至关重要， 功能具体目标2和3将检查新生儿中富集的细胞成分， 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细胞是胎儿前体细胞的想法， 起源支持这一假设的是我们观察到的胎儿外周血CD4+细胞来源于 胸腺细胞具有增强的Th2功能。第二，新生儿外周血CD4+细胞群含有 比例上，比在成人外周人群中发现的更多的近期胸腺移行细胞（RTE）。 因此，特定目标3将解决RTE是新生儿Th2功能来源的假设。 我们的研究结果支持了这一观点，即新生儿外周血CD4+细胞的功能类似于 成人的RTE。

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 1will 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 DMAmethylation 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 hypothesisthat 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.