Distinct functions for CD8 T cells in cutaneous leishmaniasis

CD8 T 细胞在皮肤利什曼病中的独特功能

• 批准号: 10565960
• 负责人: Fernanda Novais
• 金额: $ 42.21万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565960
• 关键词: Antibiotic Therapy; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Death Induction; Cell Separation; Cell physiology; Cells; Chronic; Clinical; Cutaneous; Cutaneous Leishmaniasis; Cytolysis; Cytotoxic T-Lymphocytes; Data; Dermal; Development; Disease; Disease model; Drug usage; Exhibits; Foundations; Genes; Germ-Free; Granzyme; Human; Hypoxia; Immune response; Infection; Inflammation; Inflammatory; Interferon Type II; Interleukin-1 beta; Interleukin-15; JAK1 gene; Knowledge; Leishmania; Leishmaniasis; Lesion; Mediating; Molecular; Mus; Neutrophil Infiltration; Oxygen Consumption; Parasite Control; Parasites; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Play; Proteins; Publishing; Risk; Role; Severity of illness; Signal Transduction; Skin; T-Cell Development; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Topical Antibiotic; Vaccines; comparative; cytokine; cytotoxic; cytotoxicity; draining lymph node; dysbiosis; genetic signature; healing; immunopathology; insight; lymph nodes; microbial; microbiota; mouse model; neutrophil; perforin; prevent; prognostic indicator; programs; recruit; response; single-cell RNA sequencing; skin microbiota; therapeutic development; therapy design; transcription factor

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.

项目摘要 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， 从自愈性病变到慢性衰弱性感染的表现。目前还没有疫苗 这种疾病和用于解决感染的药物通常无效。尽管寄生虫 作为疾病严重程度的重要决定因素，免疫应答本身引起大量病理。 CD 8 T细胞已显示在疾病中起双重作用，当它们产生IFN-γ时具有保护性， 但是当它们介导损伤中的炎症诱导细胞死亡时是致病的。我们发现产生IFN-γ的 保护性CD 8 T细胞仅限于引流淋巴结，而具有细胞毒性并因此具有致病性的CD 8 T细胞在疾病的实验鼠模型和患者中的利什曼病病变中被发现。我们 初步结果表明，CD 8 T细胞功能的这种二分法是对组织的反应， 这些结果表明，一旦进入微环境，产生IFN-γ的保护性CD 8 T细胞就变得溶细胞 利什曼病这种转换所涉及的因素是未知的，在这里，我们建议填补这一空白， 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 CD 8 T细胞。我们将测试缺氧、IL-1β和IL-15在促进溶细胞性T细胞发育中的作用， 确定CD 8 T细胞在淋巴结和病变内的异质性。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是一种调节溶细胞性T细胞的转录因子， 功能，并且是CD 8 T细胞介导的疾病所必需的。此外，我们还将测试Blimp-1的能力， 通过增强CD 8 T细胞向病变的募集来促进病理学。这两个目标将提供信息 有助于设计可能阻断致病性CD 8 T细胞发展的疗法。最后，在第三 我们将评估中性粒细胞和皮肤微生物群在改变皮肤微环境中的作用。我们 初步结果表明，中性粒细胞调节病变中的O2水平， 因此，CD 8 T细胞介导的疾病需要中性粒细胞和微生物群两者。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 免疫反应介导和调节皮肤利什曼病的疾病。