Mechanisms of Immune Memory Regulation by PD-1

PD-1调节免疫记忆的机制

• 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
• 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

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是我们设计针对各种传染病和癌症的有效疫苗的能力的核心。我们已经证明，免疫记忆的定量和定性特性在感染或免疫后早期就决定了，抗原的持续时间是一个关键的决定因素。我们还确定了新的细胞表面标志物，可以成功地预测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志物来区分记忆命运细胞，我们发现效应分化的程度与记忆潜力负相关。我们的研究涉及记忆命运和终末分化效应细胞的全基因组微阵列比较，有趣的是，记忆命运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假设PD-1对记忆命运的CD 8 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在CD 4 T细胞、CD 8 T细胞、B细胞、单核细胞、树突细胞等上广泛表达，我们产生了CD 8 T细胞特异性PD-1敲除小鼠，以明确PD-1信号传导在CD 8 T细胞记忆应答中的作用。在同一WT小鼠中存在野生型（WT）和PD-1敲除（KO）CD 8 T细胞的混合嵌合体环境中，我们发现PD-1 KO CD 8 T细胞在急性病毒感染后扩增并分化为与WT CD 8 T细胞类似的效应细胞。然而，它们的存活潜力存在显著差异-与WT CD 8 T细胞相比，PD-1 KO CD 8 T细胞在病原体清除后经历更大的死亡，并且从PD-1 KO CD 8 T细胞产生最小的记忆库。 这个非常集中的R 03提案的目标是双重的-目标1：确定PD-1信号何时起作用来调节记忆细胞存活。将采用全基因组转录组分析和抗体阻断的组合来确定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。目的2：确定PD-1信号如何促进记忆细胞的寿命。在该具体目标中，将评估PD-1表达对T细胞增殖维斯维斯细胞因子信号转导的抑制作用，以 了解抑制性PD-1信号是否对T细胞刺激和增殖施加“制动”，以促进记忆寿命。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理解调节免疫记忆寿命的因素方面向前迈出了重要一步，并将打开PD-1信号传导领域作为疫苗设计的新研究领域，我们希望在后续R 01提案的推动下继续进行。PHS 398/2590（Rev.06/09）