Resident Memory T cells in Leishmaniasis

开发针对细胞内微生物病原体的有效疫苗，如分枝杆菌， 弓形虫、疟原虫和利什曼病仍然是一个难以实现的目标。尽管做出了很大努力来定义 抗药性所需的机制，开发新的佐剂，并识别保护性抗原，长寿 可对感染作出反应的细胞免疫并不总是通过接种疫苗来实现的。 例如，尽管感染利什曼病后产生了强大的免疫力，但努力 研制人类利什曼病疫苗一直未获成功。缺乏成功的部分原因是 对介导保护的T细胞的了解有限。虽然我们已经确认循环中的T细胞 利什曼病中有助于免疫的亚群(1)，这些循环中的T细胞不能提供 在已经解决了一次主要感染主要乳杆菌感染的小鼠身上观察到的免疫力。使用蒙皮的组合 然而，我们发现，移植和过继转移，利什曼反应性干扰素-γ产生CD_4+T 驻留在皮肤中的细胞是最佳保护性免疫所需的缺失环节。我们建议 确定它们是如何在皮肤中产生和维持的，确定它们如何提高免疫力，以及 以利什曼病毒疫苗为靶点。这些研究对利什曼病具有重要意义，并具有广泛的应用前景。 对针对其他病原体的疫苗开发的影响。在目标1中，我们将定义以下因素 调节原发灶消退后CD4+驻留记忆T细胞在皮肤中的积聚 感染。这些研究与疫苗开发有直接关系，因为它们将定义 生成常驻存储器T细胞所需的。在目标2中，我们重点讨论常驻人员 记忆T细胞起到了保护作用。在这里，我们将识别与驻留协同的效应器T细胞 记忆T细胞介导保护，并确定驻留的记忆T细胞是否有助于放大 T效应细胞的产生。最后，在目标3中，我们将把这些信息转化为一个实验 疫苗。我们将创建一种表达利什曼病毒抗原的重组痘苗病毒，并评估 这种疫苗诱导的保护，并定性和定量地定义T细胞对 这种保护。

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 that can be generated in response to infection is not always recapitulated by vaccination. For example, in spite of the strong immunity that develops following an infection with leishmania, efforts to develop a vaccine for human leishmaniasis have been unsuccessful. Lack of success is due in part to the limited understanding of the T cells that mediate protection. While we have identified circulating T cell subsets that contribute to immunity in leishmaniasis (1), these circulating T cells fail to provide the level of immunity observed in mice that have resolved a primary infection with L. major. Using a combination of skin grafting and adoptive transfers, however, we found that leishmania-responsive IFN-γ producing CD4+ T cells resident in the skin are the missing link required for optimal protective immunity (2). We propose to identify how they are generated and maintained in the skin, determine how they promote immunity, and target them in a leishmanial vaccine. These studies are important for leishmaniasis, and have broad implications for vaccine development against other pathogens. In Aim 1 we will define the factors that regulate the accumulation of CD4+ resident memory T cells in the skin following resolution of a primary infection. These studies have direct relevance to vaccine development, as they will define what will be required for generating resident memory T cells. In Aim 2, we focus on the mechanisms by which resident memory T cells mediate protection. Here we will identify the effector T cells that synergize with resident memory T cells to mediate protection, and determine if resident memory T cells help to amplify the generation of T effector cells. Finally, in Aim 3 we will translate this information into an experimental vaccine. We will create a recombinant vaccinia virus expressing a leishmanial antigen, and assess the protection induced by this vaccine and qualitatively and quantitatively define the T cells that contribute to that protection.