Regulation of chronic viral infection by co-inhibitory pathways

描述(由申请人提供)：抗微生物T细胞反应在决定感染结果中起主要作用。慢性感染通常通过不能完全消除病原体的T细胞反应来区分。解释T细胞效应器反应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器功能与引起免疫病理的可能性之间的微妙平衡。在慢性感染的背景下，调节免疫反应以避免组织损伤可能特别重要。我们正在使用淋巴细胞性脉络膜脑膜炎病毒(LCMV)模型来研究B7：CD28家族中的抑制通路如何在慢性感染期间调节T细胞反应。我们的研究表明，PD-1及其配体PD-L1和PD-L2在慢性LCMV感染过程中直接导致T细胞耗竭和缺乏病毒控制。在体内阻断PD-1：PD-L1在慢性感染小鼠中的相互作用可以恢复T细胞功能，并导致病毒水平的大幅降低。因此，这些研究确定了T细胞耗竭的特定机制，并提示阻断这一途径可能为慢性感染提供一种新的治疗方法。由于PD-1及其配体在调节耐受性方面也起着关键作用，因此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，同时将免疫病理和自身免疫的风险降至最低。PD-L1：B7-1通路的发现使我们不禁要问，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途径，以及PD-L1：PD-1和PD-L2：PD-1相互作用，在慢性感染过程中调节病毒特异性T细胞反应和病毒控制。PD-L1可能触发比PD-1更深刻的抑制作用，因为PD-L1具有触发两种抑制相互作用的潜力。为了验证这一假说，我们的具体目的是：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之间的平衡中的相对贡献。2)分析PD-L1和PD-1对特定细胞类型在调节T细胞反应、病毒清除和免疫病理中的作用；以及3)确定PD-L2如何控制病毒免疫和免疫病理之间的平衡。我们的目标是确定最好的治疗方式来增强病毒清除，同时最大限度地减少免疫病理。

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.