Resident Memory T cells in Leishmaniasis

利什曼病中的常驻记忆 T 细胞

基本信息

批准号：
9916704
负责人：
PHILLIP SCOTT
金额：
$ 40.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-16 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916704
关键词：
Adjuvant Adoptive Transfer Antigens CD4 Positive T Lymphocytes Cell Differentiation process Cells Cellular Immunity Cutaneous Development Disease Eragrostis Future Generations Genus Mycobacterium Goals Human Immunity Immunization Infection Inflammatory Interferon Type II Interferons Leishmania Leishmania major Leishmaniasis Lesion Link Mediating Memory Methods Mus Nature Parasite Control Parasites Plasmodium Primary Infection Proteins Resistance Resolution Role Route Seeds Skin Skin graft Source T cell differentiation T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Testing Toxoplasma Translating Vaccination Vaccines Vaccinia Vaccinia virus cell motility design effector T cell migration monocyte neglected tropical diseases pathogen pathogenic microbe recruit response success tool vaccine development vaccine efficacy vaccine evaluation vaccine-induced immunity

项目摘要

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.

开发用于细胞内微生物病原体（例如分枝杆菌）的有效疫苗弓形虫，浆钠和利什曼原虫仍然是一个难以捉摸的目标。尽管为定义了电阻所需的机制，发展新的佐剂并识别受保护的抗原，长期寿命可以响应感染而产生的细胞免疫力并不总是通过疫苗接种概括。例如，尽管有强烈的免疫学在感染利什曼尼亚之后发展，但仍在努力开发人类利什曼病的疫苗并没有成功。缺乏成功的部分原因是对介导保护的T细胞的了解有限。虽然我们已经确定了循环的T细胞有助于利什曼病的免疫力的子集（1），这些循环的T细胞无法提供水平在解决了乳杆菌原发性感染的小鼠中观察到的免疫力。结合皮肤但是，嫁接和自适应转移，我们发现利什曼原虫反应性IFN-γ产生CD4+ T 皮肤中的居民是最佳保护免疫所需的缺失联系（2）。我们建议确定它们是如何生成和维持在皮肤中的，确定它们如何促进免疫力，以及将它们靶向利什人类疫苗。这些研究对利什曼病很重要，并且具有广泛的对其他病原体的疫苗发育的影响。在AIM 1中，我们将定义的因素分辨率后，调节CD4+居民记忆T细胞在皮肤中的积累感染。这些研究与疫苗开发具有直接相关性，因为它们将定义什么生成居民记忆T细胞所需的。在AIM 2中，我们专注于居民的机制记忆T细胞介导保护。在这里，我们将确定与居民协同作用的效应T细胞记忆T细胞介导保护，并确定居民记忆T细胞是否有助于放大 T效应细胞的产生。最后，在AIM 3中，我们将将这些信息转化为实验疫苗。我们将创建一种表达利什曼抗原的重组疫苗病毒，并评估该疫苗引起的保护以及定性和定量定义有助于的T细胞保护。