Distinct functions for CD8 T cells in cutaneous leishmaniasis

项目总结 皮肤利什曼病是由利什曼原虫引起的一种疾病，临床表现广泛。 从自我修复损伤到慢性衰弱感染的表现。目前还没有疫苗来预防 这种疾病，以及用来解决感染的药物往往无效。尽管寄生虫是 作为疾病严重程度的重要决定因素，免疫反应本身就会引起大量的病理变化。 CD8T细胞已被证明在疾病中起双重作用，当它们产生干扰素-γ时既具有保护性， 但当它们在病变中介导炎症诱导的细胞死亡时是致病的。我们发现产生干扰素-γ 保护性CD8T细胞仅限于引流淋巴结，而细胞毒性因而致病CD8 在这种疾病的实验小鼠模型和患者的利什曼病变中都发现了T细胞。我们的 初步结果表明，CD8T细胞功能的这种二分法是对组织的一种反应 微环境和产生干扰素-γ的保护性CD8T细胞一旦进入就会发生细胞溶解 利什曼病损。这种转换所涉及的因素是未知的，在此我们建议在 知识。在我们的第一个目标中，我们将确定组织微环境如何启动细胞溶解途径。 在CD8T细胞中。我们将测试低氧、IL-1β和IL-15在促进细胞溶解T细胞发育和 确定CD8 T细胞在淋巴结和病变内的异质性程度。在我们的第二个目标，我们 将确定是什么诱导Blimp-1的表达，Blimp-1是一种调节细胞溶解T细胞的转录因子 功能，是CD8T细胞介导疾病所必需的。此外，我们还将测试Blimp-1的能力 通过增强CD8 T细胞对病变的募集来促进病理。这两个目标都将提供信息 有助于设计可能阻止致病CD8 T细胞发展的治疗方法。最后，在第三个 目的评价中性粒细胞和皮肤微生物区系在改变皮肤微环境中的作用。我们的 初步结果表明，中性粒细胞调节病变中的O2水平，微生物区系放大中性粒细胞 CD8T细胞介导的疾病需要中性粒细胞和微生物区系的募集。总的来说， 这些研究将提供来自小鼠模型的信息，这些信息将是理解 皮肤利什曼病中调节疾病的免疫反应。

PROJECT SUMMARY Cutaneous leishmaniasis is a disease caused by leishmania parasites, and exhibits a wide range of clinical manifestations from self-healing lesions to chronic debilitating infections. Currently there are no vaccines for this disease, and the drugs used to resolve the infections are often ineffective. Although the parasites are important determinants of disease severity, the immune response itself causes a large amount of pathology. CD8 T cells have been shown to play a dual role in disease by being both protective when they produce IFN-γ, but pathogenic when they mediate inflammation-inducing cell death in lesions. We found that IFN-γ-producing protective CD8 T cells are restricted to draining lymph nodes, whereas cytotoxic and therefore pathogenic CD8 T cells are found in leishmanial lesions in both experimental murine models of the disease and in patients. Our preliminary results suggest that this dichotomy in CD8 T cell function is a response to the tissue microenvironment and that protective IFN-γ-producing CD8 T cells become cytolytic once they enter leishmanial lesions. The factors involved in this conversion are unknown, and here we propose to fill this gap in knowledge. In our first aim we will determine how the tissue microenvironment initiates the cytolytic pathway in CD8 T cells. We will test the role of hypoxia, IL-1β and IL-15 in promoting cytolytic T cell development and determine how heterogeneous the CD8 T cells are within the lymph nodes and lesions. In our second aim, we will determine what induces the expression of Blimp-1, a transcription factor that regulates cytolytic T cell function and is required for CD8 T cell-mediated disease. In addition, we will test the ability of Blimp-1 to promote pathology by enhancing CD8 T cell recruitment to lesions. Both of these aims will provide information helpful in designing therapies that might block the development of pathogenic CD8 T cells. Finally, in the third aim we will evaluate the role of neutrophils and the skin microbiota in altering the skin microenvironment. Our preliminary results suggest that neutrophils regulate O2 levels in lesions, that the microbiota amplify neutrophil recruitment and both neutrophils and the microbiota are required for CD8 T cell-mediated disease. Overall, these studies will provide information from murine models that will be foundational in understanding the immune responses mediating and regulating disease in cutaneous leishmaniasis.