Mechanisms of CD49a Expression and Resident Memory T Cell Formation in Skin.

免疫系统必须在最有可能遇到病原体的部位--上皮细胞--保护宿主 屏障器官和宿主环境之间的界限。令人兴奋的最新数据表明， 一群记忆T细胞（TRM）长期存在于外周组织中，并提供了第一批宿主细胞。 防御引起局部感染的病原体。但是，在某些设置中，内存的本地持久性 提供强大反应的T细胞是有害的。TRM被认为在当地的，经常性的 炎症性皮肤病。这项建议旨在解决我们对《公约》的理解方面的重大差距。 调节健康和疾病中皮肤TRM的机制。定义控制TRM的机制 前体在皮肤内的定位和持久性对于优化疫苗以提供局部免疫应答是重要的。 保护以及治疗，以防止不必要的炎症。引导组织间质 皮肤TRM的迁移、持续和应答将在对HSV的正常免疫应答中定义 感染和自身免疫性白癜风。虽然已知局部细胞因子微环境指导TRM 形成，抑制TRM分化/持久性的因素是未知的。该提案将调查 根据细胞因子微环境，TRM形成被促进或抑制。 最后，尽管TRM已在皮肤炎性疾病部位被鉴定，但靶向TRM是一种治疗方法。 未经测试的治疗方法。我们将使用具有临床应用的白癜风小鼠模型来研究 一种新的假说，即自身反应性TRM维持色素脱失，而自身反应性TRM的耗竭将 预防和/或改善疾病。上调途径促进T细胞的持久性， 外周组织是当前疫苗设计的关键焦点;创建方法可能同样重要。 逆转这些途径，以防止不必要的TRM积累在发炎组织内。

The immune system must defend the host at the most likely sites of pathogen encounter--the epithelial cell boundaries between barrier organs and the host's environment. Exciting recent data demonstrate that a population of memory T cells (TRM) resides long-term within peripheral tissues and provides a first line of host defense from pathogens that cause local infection. However, in some settings, the local persistence of memory T cells that provide robust response is detrimental. TRM are thought to play a key role in local, recurring inflammatory skin diseases. This proposal seeks to address significant gaps in our understanding of the mechanisms that regulate cutaneous TRM in health and disease. Defining mechanisms that control TRM precursor localization and persistence within skin will be important for optimizing vaccines to provide local protection as well as therapies to prevent unwanted inflammation. Mechanisms that direct the interstitial migration, persistence and response of cutaneous TRM will be defined in a normal immune response to HSV infection and in autoimmune vitiligo. While the local cytokine microenvironment is known to direct TRM formation, factors that inhibit TRM differentiation/persistence are unknown. This proposal will investigate the hypothesis that depending on the cytokine microenvironment TRM formation is either promoted or inhibited. Lastly, although TRM have been identified at sites of cutaneous inflammatory disease, targeting TRM is an untested therapeutic approach. We will use a mouse model of vitiligo with clinical application to investigate the novel hypothesis that autoreactive TRM maintain depigmentation, and that depletion of autoreactive TRM will prevent and/or ameliorate disease. Up-regulating pathways that promote the persistence of T cells in peripheral tissues is a critical focus of current vaccine design; it may be equally important to create approaches that reverse these pathways to prevent unwanted TRM accumulation within inflamed tissues.