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，由几种具有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，因为疾病的严重程度不是由于不受控制的寄生虫复制所致，而是由于过度的免疫反应所致。因此，如果旨在增加寄生虫杀灭的治疗同时增强炎症反应，那么它们是有害的。我们的新数据强烈表明，对巴西乳杆菌的最佳控制需要一种不仅能有效消除寄生虫，而且还能降低免疫病理学可能性的反应。我们进行了两项意想不到的观察，证明 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增加，这为研究导致患者转移病灶发展的因素提供了一个模型。 其次，我们发现，已经解决了淋巴细胞脉络膜脑膜炎病毒（LCMV）感染的小鼠维持了扩大的CD8池，并且当受到利什曼原虫攻击时，会向病变处募集大量LCMV特异性CD8 T细胞，从而导致疾病严重程度的增加。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）会促进炎症增加，这可能是由于通过称为 NKG2D 的激活受体非特异性裂解靶细胞，也可能是由于细胞因子诱导的颗粒酶 B (GrzB) 释放。这些发现表明，控制 CD8 T 细胞的致病活性可能是开发皮肤利什曼病新免疫疗法的好方法。我们提出了三个具体目标，以增进我们对该疾病的了解并为新的治疗方法奠定基础。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环境决定的，我们提出实验来确定致病性 CD8 T 细胞是否可以转化为保护性细胞。在目标 2 中，我们重点关注旁观者 CD8 T 细胞如何促进疾病增加，特别关注 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发挥保护作用。总而言之，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疗法。

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.