Regulation of murine neonatal Th2 function

小鼠新生儿 Th2 功能的调节

• 批准号: 7344845
• 负责人: REBECCA D ADKINS
• 金额: $ 36.44万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2011-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7344845
• 关键词: Address; Adult; Age; Allergens; Antigens; Asthma; CD4 Positive T Lymphocytes; Cells; Childhood; Chromatin; Developed Countries; Development; Disease; Emigrant; Epigenetic Process; Equilibrium; Event; Fluorescein-5-isothiocyanate; Frequencies; Generations; Goals; Health; Hematopoietic; Human; Hypersensitivity; Immune system; Immunity; Infant; Injection of therapeutic agent; Laboratories; Life; Maintenance; Mediating; Memory; Methylation; Molecular; Mus; Neonatal; Nucleic Acid Regulatory Sequences; Pathology; Pattern; Peripheral; Plastics; Population; Process; Regulation; Relative (related person); Source; Specificity; Testing; Th2 Cells; Thinking; Treatment Protocols; base; cell growth regulation; cell type; cytokine; demethylation; design; fetal; improved; in vivo; insight; neonate; novel strategies; prevent; response; thymocyte

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.

小鼠生命早期的 T 辅助反应，尤其是人类婴儿的过敏原特异性反应 偏向Th2功能。这种生命早期的 Th2 优势与 Th2- 的发育有关。 介导的疾病，例如过敏和哮喘。随着 Th2 介导的疾病呈上升趋势，有一个明确的 需要开发新方法来预防和治疗病理性 Th2 活动。然而，什么 目前缺乏的是对生命早期Th2功能基础的透彻理解。该信息是 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，长 该提案的长期目标是确定新生儿 Th2 反应的分子和细胞调节。 具体目标 1 将重点关注控制新生儿 Th2 功能的分子事件。我们已经生成了 令人信服的证据表明，新生儿 Th2 偏好至少部分是在表观遗传水平上受到调节的。幼稚的 与成人 CD4+ 细胞不同，新生儿 CD4+ 细胞显示 Th2 基因座关键调节区域的去甲基化。 因此，我们将进一步研究这一现象、其特殊性及其发展起源，并测试 认为 DMA 甲基化对于定义 Th2 效应器分化的发育差异至关重要， 功能。具体目标 2 和 3 将检查新生儿体内富含的强健细胞成分 Th2 活性的主要来源的候选者。首先，由于许多新生儿 CD4+ 细胞可能是 胎儿前体的直系后代，特定目标 2 将检验新生儿 Th2 细胞属于胎儿的观点 起源。对这一假设的支持来自我们的观察，即外周 CD4+ 细胞源自胎儿 胸腺细胞具有增强的Th2功能。其次，新生儿的外周CD4+群体包含 与周围成年人群中发现的相比，近期胸腺移出者（RTE）比例要高得多。 因此，具体目标 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 CD4+ 细胞的功能类似于 成人 RTE。