Resident memory T cells in leishmaniasis

描述（由申请人提供）：开发有效的细胞内微生物病原体疫苗，如分枝杆菌、弓形虫、疟原虫和利什曼原虫，仍然是一个难以捉摸的目标。尽管在确定耐药性所需的机制、开发新的佐剂和鉴定保护性抗原方面做出了大量努力，但在对病原体感染的反应中产生的长期细胞免疫并不总能通过接种疫苗来重现。利什曼病是世界范围内发生的一种被忽视的重要热带病，由几种不同的寄生虫引起，目前尚无疫苗。然而，原发性利什曼原虫感染得到解决的小鼠和人类都对再次感染具有高度抵抗力。我们发现对利什曼原虫免疫的小鼠含有大量的皮肤常驻T细胞，我们认为这可能是它们抵抗的关键因素。在这个探索性的R21中，我们建议充分表征这些T细胞，以确定它们是否将成为成功的利什曼病疫苗的重要组成部分。基于我们的发现，我们提出了两个具体的目标，这将促进我们对皮肤驻留T细胞的理解，并为疾病的新免疫方法提供基础。在Aim 1中，我们将确定皮肤定位的T细胞是否确实是皮肤中真正的常驻记忆T细胞，并将评估是什么促成了它们在皮肤中的维持。我们还将直接确定它们在免疫中的作用，方法是将它们转移到健康小鼠的皮肤中，然后进行激射实验。在Aim 2中，我们将利用观察到的牛痘病毒免疫通过皮肤划伤诱导强健的皮肤驻留T细胞群。我们将用表达保护性利什曼抗原、巯基特异性抗氧化剂的牛痘病毒免疫小鼠。这些研究将评估存在的常驻记忆T细胞，将它们与感染产生的T细胞进行比较，并确定它们是否提供保护性免疫。总之，这些是首次评估皮肤常驻T细胞在免疫任何细胞内微生物病原体中的作用的研究，并将提供有关皮肤常驻T细胞可用于疫苗开发的新信息。

DESCRIPTION (provided by applicant): The development of effective vaccines for intracellular microbial pathogens, such as mycobacteria, toxoplasma, plasmodium, and leishmania, remains an elusive goal. Despite substantial efforts to define the mechanisms required for resistance, develop new adjuvants, and identify protective antigens, the long-lived cellular immunity generated in response to pathogen infection cannot always be recapitulated by vaccination. Leishmaniasis is an important neglected tropical disease that occurs worldwide, caused by several different parasites, for which no vaccine is available. However, both mice and humans who have resolved a primary infection with leishmania are highly resistant to reinfection. We discovered that leishmania immune mice contain a population of skin resident T cells, which we believe could be a key factor in their resistance. In this exploratory R21 we propose to fully characterize these T cells, in order to determine if they will be an important component in a successful leishmanial vaccine. Based upon our finding, we propose two specific aims that will advance our understanding of skin resident T cells and provide a foundation for new immunization approaches for the disease. In Aim 1 we will determine whether the skin localized T cells are indeed bona fide resident memory T cells in the skin and will assess what contributes to their maintenance in the skin. We will also directly determine their role in immunity, by transferring them into the skin of na¿ve mice followed by challenge experiments. In Aim 2, we will take advantage of the observation that vaccinia virus immunization by skin scarification induces a robust skin resident T cell population. We will immunize mice with vaccinia virus expressing a protective leishmanial antigen, thiol-specific anti-oxidant. These studies will evaluate the resident memory T cells present, compare them with those generated by infection, and determine if they provide protective immunity. Taken together, these are the first studies to evaluate the role of skin resident T cells in immunity to any intracellular microbial pathogen, and will provide new information about skin resident T cells that can be applied to vaccine development.