Regulation of chronic viral infection by co-inhibitory pathways

描述（由申请方提供）：抗微生物T细胞应答在确定感染结果方面起主要作用。慢性感染通常通过不能完全消除病原体的T细胞反应来区分。解释这种T细胞效应器应答失败的机制才刚刚开始被理解。T细胞对感染反应的调节反映了消除微生物所需的效应子功能与引起免疫病理学的潜力之间的微妙平衡。调节免疫反应以避免组织损伤在慢性感染的情况下可能特别重要。我们正在使用淋巴细胞脉络丛脑膜炎病毒（LCMV）模型，以研究如何在B7：CD 28家族的抑制途径调节慢性感染期间的T细胞反应。我们的研究表明，PD-1及其配体PD-L1和PD-L2直接导致慢性LCMV感染期间T细胞耗竭和缺乏病毒控制。在慢性感染小鼠中体内阻断PD-1：PD-L1相互作用可恢复T细胞功能，并导致病毒水平大幅降低。因此，这些研究确定了T细胞耗竭的特定机制，并表明阻断该途径可能为慢性感染提供新的治疗方法。需要进一步的研究来确定如何最好地调节PD-1及其配体以激活抗病毒T细胞，同时最大限度地减少免疫病理学和自身免疫的风险，因为PD-1及其配体在调节耐受性方面也具有关键作用。PD-L1：B7-1通路的发现使我们思考PD-L1：PD-1和PD-L1：B7-1相互作用在控制慢性感染、T细胞耗竭和免疫病理学方面是否具有独特或重叠的作用。我们的主要假设是，新发现的PD-L1：B7-1通路以及PD-L1：PD-1和PD-L2：PD-1相互作用在慢性感染期间调节病毒特异性T细胞应答和病毒控制。PD-L1可能比PD-1触发更深刻的抑制作用，因为PD-L1有可能触发两种抑制相互作用。为了验证这一假设，我们的具体目标是：1）分析新定义的PD-L1：B7-1通路的功能意义，以及PD-L1：B7-1和PD-L1：PD-1通路在控制病毒特异性免疫和免疫病理学之间平衡方面的相对贡献。2)分析PD-L1和PD-1对特定细胞类型在调节T细胞应答、病毒清除和免疫病理学中的作用;以及3）确定PD-L2如何控制病毒免疫和免疫病理学之间的平衡。我们的目标是确定最佳的治疗方式，以提高病毒清除，同时尽量减少免疫病理学。

DESCRIPTION (provided by applicant): 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. The regulation of T cell responses to infection reflects a delicate balance between effector functions needed to eliminate the microbe and the potential to cause immunopathology. Regulating the immune response to avoid tissue damage may be particularly important in the setting of chronic infection. We are using the lymphocytic choriomeningitis virus (LCMV) model to investigate how inhibitory pathways in the B7:CD28 family regulate T cell responses during chronic infection. Our studies indicate that PD-1 and its ligands, PD-L1 and PD-L2, contribute directly to T cell exhaustion and lack of viral control during chronic LCMV infection. In vivo blockade of PD-1:PD-L1 interactions in chronically infected mice restores T cell function and leads to a substantial reduction in virus levels. Thus, these studies identify a specific mechanism of T cell exhaustion, and suggest that blockade of this pathway may provide a new therapeutic approach for chronic infections. Further studies are needed to determine how to best modulate PD-1 and its ligands to activate anti-viral T cells while minimizing the risk of immunopathology and autoimmunity, since PD-1 and its ligands also have key roles in regulating tolerance. The discovery of the PD-L1:B7-1 pathway leads us to ask whether PD- L1:PD-1 and PD-L1:B7-1 interactions have unique or overlapping roles in controlling chronic infection, T cell exhaustion, and immunopathology. Our main hypothesis is that the newly discovered PD-L1:B7-1 pathway, as well as PD-L1:PD-1 and PD-L2:PD-1 interactions, regulate virus-specific T cell responses and viral control during chronic infection. PD-L1 may trigger more profound inhibitory effects than PD-1 because PD-L1 has the potential to trigger two inhibitory interactions. To test this hypothesis, our Specific Aims are to: 1) Analyze the functional significance of the newly defined PD-L1:B7-1 pathway, and the relative contributions of the PD- L1:B7-1 and PD-L1:PD-1 pathways in controlling the balance between virus-specific immunity and immunopathology. 2) Analyze the roles of PD-L1 and PD-1 on specific cell types in regulating T cell responses, viral clearance and immunopathology; and 3) Determine how PD- L2 controls the balance between viral immunity and immunopathology. Our goal is to determine the best therapeutic modality for enhancing viral clearance while minimizing immunopathology.