Project 1: Costimulation and Regulation of Anti-viral Immunity

抗微生物T细胞反应在决定感染结果中起主要作用。 慢性感染通常以不能完全消除的T细胞反应来区分 病原体。解释这种T细胞效应器反应失败的机制只是 开始被理解了。在目前的筹资期间，我们使用了淋巴细胞 脉络膜脑膜炎病毒(LCMV)模型研究PD-1途径如何调节T细胞 在慢性感染期间的反应。我们发现PD-1途径具有多面性 在保护性免疫中的作用。我们发现，除了PD-L1，PD-L2还限制了 耗尽了T细胞。我们还表明，PD-L1在造血和非造血系统中具有不同的作用。 慢性感染期间的造血细胞。然而，我们缺乏对 PD-L1和PD-L2在特定的细胞类型上发挥作用。这项提议的一个主要目标是澄清 PD-1及其配体调节CD8 T细胞耗竭的机制 鉴于这一途径的治疗前景，它具有基本和翻译上的重要性。在……里面 此外，我们还发现了PD-1途径在保护性免疫中的新功能。我们 已经确定了PD-1通过抑制产生和调节体液免疫的作用 T滤泡调节细胞的功能。因此，我们将不仅讨论PD-1途径是如何 调节CD8 T细胞的消耗，也调节它如何控制体液免疫。此外，我们还将 PPG研究者鉴定的两个新的共抑制分子在抗微生物中的作用研究 免疫：排斥导向分子b(RGMb)和蛋白C受体(ProR)。Dr。 Freeman(核心B)确定RGMb为PD-L2的第二结合伙伴。T细胞的抢救 PD-L2缺陷小鼠的疲劳导致我们研究RGMb在慢性感染过程中的功能。 Kuchroo博士(PI，项目3)已经确定蛋白C受体(PROR)是一种新的共抑制物 分子；我们合作发现，在耗尽的CD8 T细胞上，PROCR高度表达 细胞。我们将研究proR是否调节T细胞的耗竭。我们的主要假设是PD-1 途径成员和PROCR调节急慢性保护性免疫 感染。为了验证这一假设，我们的具体目标是：1)分析PD-1及其配体如何 在急性粘膜/局部病毒感染(流感)期间调节体液免疫与 全身性感染。2)研究PD-1和ProR通路在调控中的作用 慢性LCMV感染时耗尽的CD8T细胞。我们的目标是确定如何 在慢性感染中以治疗的方式优化调节PD-1和PROCR通路，以及 制定新的策略，在急性病毒感染期间促进保护性免疫。

Anti-microbial T cell responses play a major role in determining the outcome of infection. Chronic infections are often distinguished by T cell responses that are not able to fully eliminate the pathogen. The mechanisms that explain this failure of T cell effector responses are only beginning to be understood. During the current funding period, we have used the lymphocytic choriomeningitis virus (LCMV) model to investigate how the PD-1 pathway regulates T cell responses during chronic infection. We have found that the PD-1 pathway has multifaceted roles in protective immunity. We discovered that in addition to PD-L1, PD-L2 limits responses of exhausted T cells. We also have shown that PD-L1 has distinct roles on hematopoietic and non- hematopoetic cells during chronic infection. However, we lack a mechanistic understanding of PD-L1 and PD-L2 functions on specific cell types. A major goal of this proposal is to elucidate mechanisms by which PD-1 and its ligands regulate CD8 T cell exhaustion, issues of fundamental and translational importance, given the therapeutic promise of this pathway. In addition, we have discovered a new function for the PD-1 pathway in protective immunity. We have identified a role for PD-1 in regulating humoral immunity by inhibiting the generation and function of T follicular regulatory cells. Thus, we will not only address how the PD-1 pathway regulates CD8 T cell exhaustion, but also how it controls humoral immunity. In addition, we will study roles of two novel coinhibitory molecules identified by PPG investigators in anti-microbial immunity: repulsion guidance molecule b (RGMb) and protein C receptor (PROCR). Dr. Freeman (Core B) identified RGMb as a second binding partner for PD-L2. The rescue of T cell exhaustion in PD-L2 deficient mice leads us to study RGMb function during chronic infection. Dr. Kuchroo (PI, Project 3) has identified protein C receptor (PROCR) as a novel coinhibitory molecule; in collaboration we have found that PROCR is highly expressed on exhausted CD8 T cells. We will study if PROCR regulates T cell exhaustion. Our main hypothesis is that PD-1 pathway members and PROCR regulate protective immunity during acute and chronic infections. To test this hypothesis, our Specific Aims are to: 1) Analyze how PD-1 and its ligands regulate humoral immunity during acute mucosal/localized viral infection (influenza) versus systemic infection (LCMV). 2) Investigate roles of the PD-1 and PROCR pathways in controlling exhausted CD8 T cells during chronic LCMV infection. Our goals are to determine how to optimally modulate the PD-1 and PROCR pathways therapeutically in chronic infection, and develop new strategies to promote protective immunity during acute viral infections.