Unconventional T cell activities in young animals

描述(由申请人提供)：有强有力的证据表明，对哮喘等过敏症的敏感性是由于早期生命中免疫反应的失调造成的。这迫使我们更好地了解早期生命的免疫反应，特别是干扰素-γ的表达，这是一种能够下调过敏T细胞反应的细胞因子。我们最近发现，在早期生命中，非常规T细胞，特别是γ-β细胞，是干扰素-γ的重要来源，幼鼠依赖这些细胞对粘膜感染进行初级保护。因此，在生命早期，非常规T细胞的实验性上调是否会促进干扰素-γ的产生，从而改变对过敏的易感性，这是合乎逻辑的。为了做到这一点，小鼠将被感染一种激活伽马三角洲细胞的自然肠道病原体，然后评估它们对食物过敏和呼吸道过敏的敏感性。肠道，而不是肺，被选为非传统T细胞激活的主要目标，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则。然而，如果该方案成功地控制了过敏，它将为尝试直接调节肺中的非常规T细胞(这超出了本应用的范围)或使用非感染性方案来更全面地调节非常规T细胞奠定重要基础，这是目标2和3的主题。尽管小鼠和人类儿童的免疫系统在成熟状态上有所不同，但提供的数据表明，人类伽马三角洲细胞与早期生命中干扰素伽马的产生有关。因此，目标4将检验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.