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：
8665383
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8665383
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）：了解如何形成免疫记忆是我们设计有效疫苗针对各种传染病和癌症的能力的核心。我们已经表明，免疫记忆的定量和定性特性是在感染或免疫后尽早确定的，并且抗原的持续时间是关键的决定因素。我们还确定了可以在T细胞扩展的初始阶段成功预测记忆结果的新型细胞表面标记。此外，使用这些细胞表面标记来区分记忆成本的细胞，我们发现效应子分化的程度与记忆电位负相关。我们的研究涉及全基因组微阵列的比较，对记忆的和终末分化的效应细胞进行了有趣的效果，表明记忆效应子在其表面上表达了较高水平的抑制性受体，程序性死亡-1（PD-1）。该观察结果促使我们假设PD-1在记忆符号的CD8 T细胞上施加制动器，以防止过度刺激并促进记忆分化。由于PD-1在CD4 T细胞，CD8 T细胞，B细胞，单核细胞，树突状细胞等上广泛表达，因此我们生成CD8 T细胞特异性PD-1基因敲除小鼠，以专门解决PD-1信号在CD8 T细胞存储器反应中的作用。在混合嵌合体设置中，在同一WT小鼠中存在野生型（WT）和PD-1基因敲除（KO）CD8 T细胞，我们发现PD-1 KO CD8 T细胞在急性病毒感染后膨胀并区分了类似于WT CD8 T细胞的效应细胞。然而，与WT CD8 T细胞相比，它们的生存潜力存在巨大差异-PD-1 KO CD8 T细胞从PD-1 KO CD8 T细胞中产生了更大的死亡和最小记忆库。这个非常重点的R03提案的目标是两倍 - 目标1：确定PD-1信号何时起作用以调节记忆细胞存活。将使用全基因组转录组分析和抗体阻滞的组合来确定在调节急性感染过程中调节免疫记忆寿命的PD-1信号的时间和来源。目标2：确定PD-1信号如何促进记忆细胞的寿命。在这个具体目的中，PD-1表达对T细胞增殖的抑制作用将评估为细胞因子信号转导至了解抑制性PD-1信号是否在T细胞刺激和增殖上发挥“制动器”以促进记忆寿命。虽然PD-1在调节免疫病理学在慢性感染中的作用已经确定，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对调节免疫记忆寿命的因素的理解迈出的重要一步，并将破解PD-1信号传导的领域，作为疫苗设计的新研究领域，我们希望在后续的后续R01提案的助理下追求这一点。 PHS 398/2590（修订版06/09）页面延续格式页面