Mechanisms of Immune Memory Regulation by PD-1

PD-1调节免疫记忆的机制

基本信息

批准号：
8584096
负责人：
Surojit Sarkar
金额：
$ 7.45万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-24 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584096
关键词：
Acquired Immunodeficiency Syndrome Acute Address Antibodies Antigens Area B-Lymphocytes Bacterial Infections Breeding CD28 gene CD4 Positive T Lymphocytes CD8B1 gene Cell Surface Receptors Cell Survival Cell surface Cells Cessation of life Chimera organism Chronic Chronic Disease Communicable Diseases Cytokine Signaling Data Defect Dendritic Cells Effector Cell Environment Equilibrium Exhibits Future Gene Expression Profile Gene Expression Profiling Generations Goals Health Hepatitis C virus Immune Immunity Immunization Immunologic Memory Infection Inflammatory Investigation Knock-out Knockout Mice Knowledge Life Ligands Longevity Maintenance Malaria Malignant Neoplasms Memory Mus Outcome Principal Investigator Property Receptor Signaling Regulation Research Role Signal Transduction Source Staging Stimulus Surface T cell response T memory cell T-Cell Proliferation T-Cell Receptor T-Lymphocyte Textbooks Time Transgenic Mice Tuberculosis Ursidae Family Vaccination Vaccine Design Vaccines Virus Diseases Wild Type Mouse adaptive immunity cell type cytokine design follow-up genome-wide global health head-to-head comparison health economics immunopathology imprint insight monocyte novel pathogen prevent programs receptor research study response tool tumor

项目摘要

DESCRIPTION (provided by applicant): Understanding how immunological memory is formed is central to our ability to design efficacious vaccines against a variety of infectious diseases ad cancer. We have shown that quantitative and qualitative properties of immunologic memory are decided early after infection or immunization, and that the duration of antigen is a key determinant. We also identified novel cell surface markers that can successfully predict memory outcome during initial stages of T cell expansion. Moreover, using these cell surface markers to distinguish memory- fated cells, we found that the extent of effector differentiation correlates negatively with memory potential. Our studies involving genome-wide microarray comparisons of memory-fated and terminally differentiated effector cells intriguingly revealed that memory-fated effectors expressed higher levels of inhibitory receptor, programmed death-1 (PD-1) on their surface. This observation prompted us to hypothesize that PD-1 exerts brakes on memory-fated CD8 T cells to prevent overstimulation and promote memory differentiation. Because PD-1 is expressed widely on CD4 T cells, CD8 T cells, B cells, monocytes, dendritic cells, etc., we generated CD8 T cell-specific PD-1 knockout mice, to specifically address the role of PD-1 signaling in CD8 T cell memory responses. In a mixed chimera setting where wild-type (WT) and PD-1 knockout (KO) CD8 T cells were present in the same WT mouse, we found that PD-1 KO CD8 T cells expanded and differentiated into effector cells similar to WT CD8 T cells following an acute viral infection. However, there was a dramatic difference in their survival potential - PD-1 KO CD8 T cells underwent greater death after pathogen clearance and minimal memory reservoirs were generated from PD-1 KO CD8 T cells compared to WT CD8 T cells. The goal of this very focused R03 proposal is two-fold - Aim 1: To determine when PD-1 signals function to regulate memory cell survival. A combination of genome-wide transcriptome analyses and antibody blockade will be employed to determine the timing and source of PD-1 signals in regulating longevity of immune memory during acute infections. Aim 2: To determine how PD-1 signals promote longevity of memory cells. In this specific aim, inhibitory effects of PD-1 expression on T cell proliferation vis a vis cytokine signal transduction will be evaluated to understand whether inhibitory PD-1 signals exert "brakes" on T cell stimulation and proliferation to promote memory longevity. While the role of PD-1 in regulating immunopathology in chronic infections is well established, its function in acute infections is not known. When completed, these studies will represent a major step forward in our understanding of factors regulating longevity of immunologic memory, and will crack open the field of PD-1 signaling as a novel research area for vaccine design, which we hope to pursue under the auspice of a follow-up R01 proposal. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

描述（由申请人提供）：了解免疫记忆是如何形成的对于我们设计针对各种传染病和癌症的有效疫苗的能力至关重要。我们已经证明，免疫记忆的定量和定性特性是在感染或免疫后早期决定的，并且抗原的持续时间是关键的决定因素。我们还发现了新的细胞表面标记物，可以成功预测 T 细胞扩增初始阶段的记忆结果。此外，使用这些细胞表面标记来区分记忆细胞，我们发现效应细胞分化的程度与记忆潜力呈负相关。我们的研究涉及记忆注定效应细胞和终末分化效应细胞的全基因组微阵列比较，有趣的是，记忆注定效应细胞在其表面表达更高水平的抑制性受体程序性死亡-1 (PD-1)。这一观察结果促使我们推测 PD-1 会对记忆相关的 CD8 T 细胞施加制动，以防止过度刺激并促进记忆分化。由于PD-1广泛表达于CD4 T细胞、CD8 T细胞、B细胞、单核细胞、树突状细胞等，我们生成了CD8 T细胞特异性PD-1敲除小鼠，以特异性解决PD-1信号传导的作用CD8 T 细胞记忆反应。在野生型 (WT) 和 PD-1 敲除 (KO) CD8 T 细胞存在于同一 WT 小鼠体内的混合嵌合体环境中，我们发现 PD-1 KO CD8 T 细胞扩增并分化为与 WT 类似的效应细胞急性病毒感染后的 CD8 T 细胞。然而，它们的生存潜力存在显着差异——与 WT CD8 T 细胞相比，PD-1 KO CD8 T 细胞在病原体清除后经历了更大的死亡，并且 PD-1 KO CD8 T 细胞产生的记忆库最少。这个非常集中的 R03 提案有两个目标 - 目标 1：确定 PD-1 信号何时发挥作用来调节记忆细胞的存活。将采用全基因组转录组分析和抗体阻断相结合来确定 PD-1 信号在急性感染期间调节免疫记忆寿命的时间和来源。目标 2：确定 PD-1 信号如何促进记忆细胞的寿命。在此具体目标中，将评估 PD-1 表达相对于细胞因子信号转导对 T 细胞增殖的抑制作用，以了解抑制性 PD-1 信号是否对 T 细胞刺激和增殖产生“刹车”，从而促进记忆寿命。虽然 PD-1 在慢性感染中调节免疫病理学的作用已得到充分证实，但其在急性感染中的功能尚不清楚。完成后，这些研究将代表我们在了解调节免疫记忆寿命的因素方面向前迈出了重要一步，并将开辟 PD-1 信号传导领域作为疫苗设计的一个新研究领域，我们希望在该领域的支持下进行研究后续 R01 提案。 PHS 398/2590（修订版 06/09）页面延续格式页面