Protective and Pathologic Roles for CD8+ T cells in Leishmaniasis

描述（由申请人提供）：利什曼病是一种重要的被忽视的热带疾病，在世界范围内发生，由几种不同特征的寄生虫引起。L.巴西利什曼病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不受控制的寄生虫复制，而是由于过度的免疫反应。因此，设计用于增加寄生虫杀灭的治疗剂如果同时增强炎症反应则是有害的。我们的新数据有力地表明，L。巴西寄生虫需要一种不仅能有效消除寄生虫，而且能降低免疫病理学可能性的反应。我们有两个意想不到的观察结果表明，CD8 T细胞有助于利什曼原虫免疫病理学。首先，我们发现不受调节的CD8 T细胞介导严重的穿孔素依赖性病理，这与CD8 T细胞杀死感染细胞有关。此外，我们还发现CD8 T细胞促进寄生虫转移的增加，这为研究导致患者转移性病变发展的因素提供了模型。 第二，我们发现，已经解决了淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染的小鼠保持了扩大的CD8库，当用利什曼原虫攻击时，招募大量LCMV特异性CD8 T细胞到病变，疾病严重程度增加。与可以杀死利什曼原虫感染的靶细胞的利什曼原虫特异性CD8 T细胞相反，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，这是由于靶细胞通过称为NKG 2D的活化受体的非特异性裂解，或由于奎宁诱导的颗粒酶B（Grz B）释放。这些发现表明，控制CD8 T细胞的致病活性可能是开发新的皮肤利什曼病免疫疗法的一个很好的方法。我们提出了三个具体目标，以促进我们对疾病的理解，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，CD8 T细胞的功能是由细胞因子的环境，我们提出的实验，以确定是否致病的CD8 T细胞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，特别是关注NKG2D和GzmB的作用。最后，在目标3中，我们将确定CD8 T细胞如何在原发性感染消退后变得具有保护性。总之，这些研究将提供有关这种疾病的新信息，这些信息可以转化为新的治疗方法。

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.