Protective and Pathologic Roles for CD8+ T cells in Leishmaniasis

CD8 T 细胞在利什曼病中的保护和病理作用

• 批准号: 8895257
• 负责人: PHILLIP SCOTT
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-21 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895257
• 关键词: Antigens; CD8B1 gene; Cell physiology; Cells; Characteristics; Cutaneous; Cutaneous Leishmaniasis; Cytolysis; Data; Development; Disease; Disease Progression; Down-Regulation; Effector Cell; Environment; Foundations; Future; Goals; Granzyme; Human; Immune; Immune response; Immunity; Immunotherapy; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-10; Interleukin-12; Interleukin-15; Intrinsic factor; Leishmania; Leishmaniasis; Lesion; Ligands; Link; Lymphocytic choriomeningitis virus; Mediating; Memory; Metastatic Lesion; Modeling; Mus; Neoplasm Metastasis; Parasites; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Production; Recruitment Activity; Relative (related person); Resolution; Role; Severities; Severity of illness; Signal Transduction; Site; Skin; Specificity; T cell differentiation; T-Lymphocyte; Testing; Therapeutic; Tissues; Transcription Repressor/Corepressor; Translating; Up-Regulation; cell killing; cytokine; cytotoxic; design; immunopathology; killings; lymph nodes; macrophage; neglected tropical diseases; novel; novel therapeutic intervention; pathogen; perforin; public health relevance; receptor; receptor expression; research study; response; secondary infection; skin lesion

DESCRIPTION (provided by applicant): Leishmaniasis is an important neglected tropical disease that occurs worldwide, and is caused by several different parasites with different characteristics. L. braziliensis infections are particularly distinct from other forms of leishmaniasis, since disease severity is not due to uncontrolled parasite replication, but rather t an exaggerated immune response. Thus, therapeutics designed to increase parasite killing are detrimental if they concomitantly enhance inflammatory responses. Our new data strongly suggests that optimal control of L. braziliensis requires a response that not only effectively eliminates the parasite, but also reduces the potential for immunopathology. We have made two unexpected observations demonstrating that CD8 T cells contribute to leishmanial immunopathology. First, we find that unregulated CD8 T cells mediate severe perforin-dependent pathology, which is associated with CD8 T cell killing of infected cells. Furthermore, we also find that CD8 T cells promote increased metastasis of the parasites, which provides a model to investigate the factors contributing to the development of metastatic lesions in patients. Second, we find that mice that have resolved an infection with lymphocytic choriomeningitis virus (LCMV) maintain an expanded CD8 pool and, when challenged with Leishmania, recruit large numbers of LCMV specific CD8 T cells to the lesions, with an associated increase in disease severity. In contrast to Leishmania-specific CD8 T cells that can kill Leishmania infected target cells, we hypothesize that these LCMV specific CD8 T cells (or bystander T cells) promote increased inflammation either due to non-specific lysis of target cells via an activating receptor known as NKG2D, or due to cytokine-induced release of granzyme B (GrzB). These findings suggest that control of the pathogenic activity of CD8 T cells might be a good approach for developing new immunotherapies for cutaneous leishmaniasis. We propose three specific aims to advance our understanding of the disease and provide a foundation for new therapeutic approaches. In Aim 1 we will evaluate how the lesion environment influences CD8 function. We find that CD8 T cell function is determined by the cytokine milieu and we propose experiments to determine if pathogenic CD8 T cells can be converted to protective cells. In Aim 2, we focus on defining how the bystander CD8 T cells promote increased disease, particularly focusing on the role of NKG2D and GzmB. Finally, in Aim 3 we will determine how CD8 T cells become protective following resolution of a primary infection. Taken together, these studies will provide new information about this disease that can be translated into new therapies.

描述(申请人提供)：利什曼病是一种重要的被忽视的热带疾病，发生在世界各地，由几种不同特征的不同寄生虫引起。巴西利什曼原虫感染与其他形式的利什曼病特别不同，因为疾病的严重性不是由于寄生虫的不受控制的复制，而是由于过度的免疫反应。因此，如果旨在增加寄生虫杀伤力的疗法同时增强炎症反应，那么它们是有害的。我们的新数据有力地表明，对巴西钩端螺旋体的最佳控制需要一种反应，不仅要有效地消除寄生虫，而且要减少免疫病理的可能性。我们做了两个意想不到的观察，证明CD8T细胞在利什曼免疫病理中起作用。首先，我们发现非调控的CD8T细胞介导了严重的穿孔素依赖的病理，这与CD8T细胞对感染细胞的杀伤有关。此外，我们还发现CD8T细胞促进寄生虫转移的增加，这为研究导致患者转移病变的因素提供了一个模型。 其次，我们发现，解决了淋巴细胞性脉络膜脑膜炎病毒(LCMV)感染的小鼠保持了扩大的CD8池，当受到利什曼原虫攻击时，会招募大量LCMV特异性CD8 T细胞到病变处，并伴随着疾病严重程度的增加。与能够杀死利什曼原虫感染的靶细胞的利什曼原虫特异性CD8 T细胞不同，我们假设这些LCMV特异性CD8 T细胞(或旁观者T细胞)促进炎症增加，这要么是由于靶细胞通过激活受体NKG2D的非特异性裂解，要么是由于细胞因子诱导颗粒酶B(GrzB)的释放。这些结果表明，控制CD8T细胞的致病活性可能是开发皮肤利什曼病免疫治疗新方法的一条很好的途径。我们提出了三个具体目标，以促进我们对这种疾病的理解，并为新的治疗方法提供基础。在目标1中，我们将评估病变环境如何影响CD8功能。我们发现CD8T细胞的功能是由细胞因子环境决定的，我们建议进行实验，以确定致病的CD8T细胞是否可以转化为保护性细胞。在目标2中，我们专注于定义旁观者CD8 T细胞如何促进疾病增加，特别是NKG2D和GzmB的作用。最后，在目标3中，我们将确定CD8 T细胞在原发感染消退后如何变得具有保护性。总而言之，这些研究将提供关于这种疾病的新信息，这些信息可以转化为新的治疗方法。