Synergies among inhibitory receptors in tolerance, cancer and antiviral immunity

描述（由申请方提供）：抑制性受体PD 1和LAG 3在调节免疫耐受和预防自身免疫中协同作用。然而，它们也限制了肿瘤清除和对慢性病毒感染的杀菌免疫。PD 1/LAG 3介导T细胞内在控制，但也调节调节性T细胞（Tcells）的发育、稳态和功能。因此，抑制性受体对于维持免疫控制是至关重要的，但也是有效抗肿瘤和抗病毒免疫的主要障碍。我们最近的研究强调了PD 1和LAG 3在各种疾病环境中的协同利用，包括自身免疫，肿瘤和慢性病毒感染。而缺乏PD 1或LAG 3的小鼠表现出最小的免疫病理学，缺乏PD 1和LAG 3的小鼠发展致命的全身性自身免疫性疾病。我们还表明，PD 1和LAG 3的组合阻断可以重振慢性病毒感染小鼠中耗尽的T细胞，并诱导预先存在肿瘤的小鼠完全缓解。本PPG的主要目标和长期目的是确定关键免疫群体中抑制性受体的相对贡献和相互协同作用。该计划项目的范围将侧重于PD 1和LAG 3在调节CD 4 + T细胞，CD 8 + T细胞和TcB调节耐受性和自身免疫（项目1），肿瘤免疫（项目2）和慢性病毒感染（项目3）中的相互作用。我们的中心假设是“PD 1和LAG 3途径通过细胞和分子串扰协同作用，导致重叠和独特的机制，共同调节自身免疫，癌症和慢性病毒感染中的CD 4 + T细胞，CD 8 + T细胞和Treg功能”。鉴于PD 1/LAG 3由所有T细胞亚群表达，目前尚不清楚PD 1/LAG 3的缺失对特定疾病背景中特定细胞类型的影响。该PPG的主要优势是可获得独特的工具，其将促进从特定T细胞亚群中组成性地或以时间控制的方式“手术”删除PD 1和/或LAG 3。本PPG将由四个核心支持：管理（核心A）、突变小鼠（核心B）、功能基因组学和计算生物学（核心C）以及免疫病理学核心（核心D）。

DESCRIPTION (provided by applicant): The inhibitory receptors PD1 and LAG3 synergize in the regulation of immune tolerance and prevention of autoimmunity. However, they also limit tumor clearance and sterilizing immunity to chronic viral infections. PD1/LAG3 mediate T cell intrinsic control, but also modulate the development, homeostasis and function of regulatory T cells (Tregs). Thus, inhibitory receptors are critical for maintaining immune control but also represent a major barrier to effective anti-tumor and anti-viral immunity. Our recent studies have highlighted the synergistic utilization of PD1 and LAG3, in a variety of disease settings including autoimmunity, tumors and chronic viral infections. Whereas mice lacking either PD1 or LAG3 alone exhibit minimal immunopathology, mice lacking both PD1 and LAG3 develop lethal systemic autoimmune disease. We have also shown that combinatorial blockade of PD1 and LAG3 can reinvigorate exhausted T cells in mice with chronic viral infections and induce complete remission in mice with pre-existing tumors. The primary goal and long-term objective of this PPG is to determine the relative contribution of, and synergistic interaction between, inhibitory receptors in critical immune populations. The scope of the program project will focus on the interplay between PD1 and LAG3 in regulating CD4+ T cells, CD8+ T cells and Tregs in the modulation of tolerance and autoimmunity (Project 1), tumor immunity (Project 2) and chronic viral infection (Project 3). Our central hypothesis is that "PD1 and LAG3 pathways synergize through cellular and molecular crosstalk leading to both overlapping and unique mechanisms that collectively regulate CD4+ T cell, CD8+ T cell and Treg function in autoimmunity, cancer and chronic viral infections". Given that PD1/LAG3 are expressed by all T cell subsets, it is not clear what impact the loss of PD1/LAG3 has on a particular cell type in a particular disease setting. A major strength of this PPG is the available of unique tools that will facilitate the `surgical' deletion of PD1 and/or LAG3 from specific T cell subpopulations constitutively or in a temporally controlled manner. This PPG will be supported by four cores; Administrative (Core A), Mutant Mouse (Core B), Functional Genomics and Computational Biology (Core C), and Immunopathology Cores (Core D).