Resident Memory T cells in Leishmaniasis

针对细胞内微生物病原体如分枝杆菌的有效疫苗的开发， 弓形虫、疟原虫和利什曼原虫，仍然是一个难以捉摸的目标。尽管作出了大量努力， 耐药所需的机制，开发新的佐剂，并确定保护性抗原， 可响应感染而产生的细胞免疫并不总是通过疫苗接种重现。 例如，尽管在感染利什曼原虫后产生了强免疫力，但仍努力 但是，人类利什曼病疫苗的开发一直不成功。缺乏成功的部分原因是 对介导保护作用的T细胞的了解有限。虽然我们已经确定了循环T细胞 在利什曼病（1）中有助于免疫的亚群，这些循环T细胞不能提供 在已经解决了L.少校使用皮肤和 然而，我们发现利什曼病应答性IFN-γ产生的CD 4 + T细胞 驻留在皮肤中的细胞是最佳保护性免疫所需的缺失环节（2）。我们建议 确定它们如何在皮肤中产生和维持，确定它们如何促进免疫力， 用利什曼原虫疫苗来对付他们这些研究对利什曼病很重要， 对其他病原体疫苗开发的影响。在目标1中，我们将定义 调节CD 4+驻留记忆T细胞在皮肤中的积累， 感染这些研究与疫苗开发直接相关，因为它们将确定 这是产生常驻记忆T细胞所必需的。在目标2中，我们关注的是居民 记忆T细胞介导保护作用。在这里，我们将确定与常驻T细胞协同作用的效应T细胞。 记忆T细胞介导的保护，并确定是否驻留记忆T细胞有助于放大 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实验性的 疫苗我们将创建一个表达利什曼原虫抗原的重组牛痘病毒，并评估其对利什曼原虫感染的影响。 保护诱导这种疫苗和定性和定量定义T细胞，有助于 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.