T Cell Tolerance in Neonates

新生儿 T 细胞耐受性

• 批准号: 7749204
• 负责人: HABIB ZAGHOUANI
• 金额: $ 17.61万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749204
• 关键词: Address; Adult; Allergens; Allergic Reaction; Allogenic; Antigens; Apoptosis; Birth; C57BL/6 Mouse; Cells; Cessation of life; Child; Cytokine Receptors; Development; Donor person; Environment; Equilibrium; Exposure to; Graft Rejection; Human; Hypersensitivity; Immune response; Immune system; Immunity; In Vitro; Infant; Infection; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Knock-in Mouse; Life; Lymphocyte; Mediating; Modeling; Mus; Neonatal; Newborn Infant; Play; Predisposition; Reaction; Regulation; Rodent; Role; Signal Transduction; Splenocyte; Staging; Staining method; Stains; System; T-Cell Receptor; T-Lymphocyte; Testing; Th1 Cells; Th2 Cells; Time; Transgenic Organisms; Transplantation Tolerance; Up-Regulation; Vaccines; base; cytokine; fetal; in vivo; microbial; neonatal exposure; neonate; public health relevance; receptor expression; research study; response; tool

DESCRIPTION (provided by applicant): Neonatal tolerance represents an immune response that lacks Th1 cells but displays an indubitable bias towards Th2. This provides an environmental pre-disposition to allergies and infections. Recently, we developed a neonate-to-neonate T cell receptor (TCR) transgenic transfer model that tracks T cells in vivo and overcomes the limitations associated with the neonatal system. We then used this model to investigate the mechanism(s) underlying the lack of Th1 and excess of Th2 cells in the response of the newborn. The findings indicated that both Th1 and Th2 cells develop upon priming with antigen on the day of birth. However, rechallenge with antigen yields secondary responses in which the Th2 cells respond and produce IL-4 but the Th1 cells up-regulate IL-13R?1 and undergo apoptosis. Moreover, we found that IL-13R?1 associates with IL- 4R? to form an IL-4R?/ IL-13R?1 heteroreceptor that IL-4 from Th2 cells uses to drive apoptosis of Th1 lymphocytes. Further analysis indicated that when adult T cells are transferred into one-day-old Balb/c mice and primed with antigen within this neonatal environment they do not up-regulate IL-13R?1 chain or undergo apoptosis. Instead, the adult T cells develop both primary and secondary Th1 response. Given that IL-4R1 is constitutively expressed on Th1 cells but IL-13R?1 can be induced only during the neonatal stage and Th2- biased neonatal immunity develops in both Th1- and Th2 prone mice we postulate that IL-13R?1 expression is under developmental regulation that controls the formation of IL-4R1/IL-13R?1 heteroreceptor which mediates the Th2 bias of neonatal immunity in both Th1- and Th2-prone mice. To address this hypothesis we propose to generate an IL-13R?1-GFP knock-in mouse to further overcome the limitations associated with the newborn and utilize this tool to determine whether IL-13R?1 expression is subject to developmental regulation at the fetal and neonatal stages. Also, we will utilize the IL-13R?1-GFP mice to determine whether IL-13R?1 up- regulation on neonatal Th1 cells occurs in Th1-prone C57BL/6 mice and allows for the formation of IL-4R?/IL- 13R?1 heteroreceptor to be utilized by IL-4 to drive apoptosis of Th1 cells leading to Th2 biased neonatal immunity. PUBLIC HEALTH RELEVANCE: More than 5 decades ago Sir Medawar demonstrated that rodents injected at birth with splenocytes from a genetically different donor were able to accept transplants from that donor as an adult. These landmark experiments suggested that neonatal exposure to antigen leads to tolerance of this antigen during a later encounter. Ever since, the neonatal period was thought of as a window during which T cell tolerance is feasible and the approach has proven useful for understanding allogeneic reactions, graft rejection and transplantation tolerance. However, recent advances in this field indicated that immunity develops in the neonate but the responses lack Th1 cells and manifest an indubitable bias towards Th2 cells. This unbalanced response likely sustains susceptibility to microbial infections and allergic reactions. Understanding the function of the neonatal immune system could facilitate development of strategies to balance Th1 and Th2 responses and overcome the susceptibility of the neonate to allergic reactions and microbial infections.

描述（由申请人提供）：新生儿耐受性代表缺乏Th1细胞但对TH2的不可估力的偏置的免疫反应。这为过敏和感染提供了环境预求的。最近，我们开发了一种新生儿到神经的T细胞受体（TCR）转基因转移模型，该模型在体内跟踪T细胞并克服与新生儿系统相关的局限性。然后，我们使用该模型来研究新生儿反应中缺乏Th1和Th2细胞过量的机制。研究结果表明，在出生当天用抗原启动时，Th1和Th2细胞都会出现。然而，用抗原进行补充可产生次要反应，其中Th2细胞反应并产生IL-4，但Th1细胞上调IL-13R？1并经历凋亡。此外，我们发现IL-13R？1与IL-4R的合伙人？要形成IL-4R？/ IL-13R？1杂型受体，该杂质从Th2细胞中使用的IL-4用于驱动Th1淋巴细胞的凋亡。进一步的分析表明，当成年T细胞转移到一日大的BALB/C小鼠中并在这种新生儿环境中用抗原启动时，它们不会上调IL-13R？1链或凋亡。取而代之的是，成年T细胞会产生初级和次级TH1反应。鉴于IL-4R1在Th1细胞上是组成型表达的，但是IL-13R？1只能在新生儿阶段诱导，而Th2-偏置的新生儿免疫在Th1-和Th2易于的th2易发小鼠中都会发展出来，我们假设IL-13R？1表达是在控制IL-4R1/IL-13R的形成的发育调节下，介导Th1-和Th2易于的小鼠中新生儿免疫的Th2偏置的杂感受体。为了解决这一假设，我们建议生成IL-13R？1-GFP敲入小鼠，以进一步克服与新生儿相关的局限和新生儿阶段。另外，我们将利用IL-13R？1-GFP小鼠来确定对新生儿Th1细胞的IL-13R？1上调节是否发生在Th1-易发的C57BL/6小鼠中，并允许形成IL-4R？/IL？ -13R？1杂质受IL-4用于驱动Th1细胞的凋亡，从而导致Th2偏置新生儿免疫。公共卫生相关性：超过5年前的Medawar爵士证明，在遗传上不同的捐赠者出生时注射脾脏的啮齿动物能够接受该捐赠者的移植物。这些具有里程碑意义的实验表明，新生儿暴露于抗原会导致这种抗原的耐受性。从那时起，新生儿时期就被认为是可行的T细胞耐受性的窗口，并且该方法已被证明可用于理解同种异体反应，移植排斥和移植耐受性。然而，该领域的最新进展表明，新生儿的免疫力发展，但反应缺乏Th1细胞，并且对Th2细胞表现出不可抑制的偏见。这种不平衡的反应可能会维持对微生物感染和过敏反应的敏感性。了解新生儿免疫系统的功能可以促进制定平衡Th1和Th2反应的策略，并克服新生儿对过敏反应和微生物感染的敏感性。