Unconventional T cell activities in young animals

描述（由申请人提供）：有大量证据表明，对过敏（如哮喘）的敏感性是由于生命早期免疫反应失调所致。这迫使我们更好地了解早期的免疫反应，特别是干扰素γ（IFN γ）的表达，这是一种能够下调过敏性T细胞反应的细胞因子。我们最近已经表明，在生命早期，非常规T细胞，特别是γ δ细胞，是IFN γ的重要来源，年轻的小鼠依赖于这些细胞的主要保护粘膜感染。因此，这是合乎逻辑的，问是否在生命早期的非常规T细胞的实验性上调将促进IFN γ的生产，将改变过敏的易感性。为了实现这一点，小鼠将被激活γ δ细胞的天然肠道病原体感染，然后评估它们对食物过敏和气道超敏反应的易感性。肠道，而不是肺，已被选为非常规T细胞活化的主要目标，因为适当的自然感染系统已经到位。简而言之，申请的第一个目的是证明原理。然而，如果该方案成功地调节变态反应，它将为尝试直接调节肺中的非常规T细胞（这超出了本申请的范围）或使用非感染性方案更全面地调节非常规T细胞奠定重要基础，这是目的2和3的主题。虽然年轻的小鼠和人类儿童的免疫系统在他们的成熟状态不同，数据显示，人类γ δ细胞的相关性，在生命早期的IFN γ的生产。因此，目标4将研究我们在动物模型中开发的策略在多大程度上可以实际应用于人类。

DESCRIPTION (provided by applicant): There is a strong body of evidence that the sensitivity to allergies, such as asthma, results from a dysregulation of immune responses in early life. This obliges us to better understand early life immune responses, and in particular, the expression of interferon gamma (IFN gamma), a cytokine with the capacity to down-regulate allergic T cell responses. We have recently shown that in early life, unconventional T cells, in particular gamma delta cells, are an important source of IFN gamma, and that young mice depend on such cells for primary protection against mucosal infection. Therefore, it is logical to ask whether the experimental up-regulation of unconventional T cells in early life will promote IFN gamma production that will alter the susceptibility to allergy. To accomplish this, mice will be infected with a natural gut pathogen that activates gamma delta cells, and their susceptibility then assessed to food allergy, and to airway hypersensitivity. The gut, rather than the lung, has been chosen as the primary target of unconventional T cell activation because the appropriate natural infection system is in place. In short, the first aim of the application is a proof of principle. Nevertheless, should the protocol successfully regulate allergy, it will lay an important foundation to attempt to regulate unconventional T cells directly in the lung (which is beyond the scope of this application) or to use non-infectious protocols to regulate unconventional T cells more globally, which is the subject of Aims 2 and 3. Although the immune systems of young mice and human children differ in their states of maturity, data are presented that show the relevance of human gamma delta cells to the production of IFN gamma in early life. Thus, Aim 4 will examine the degree to which the strategies that we develop in the animal model may be practically applied to humans.