PD-L1 interacts with CD80 and PD-1 to regulate GVHD and GVL activity

PD-L1 与 CD80 和 PD-1 相互作用调节 GVHD 和 GVL 活性

基本信息

批准号：
10335189
负责人：
Defu Zeng
金额：
$ 38.8万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335189
关键词：
Acute Acute Graft Versus Host Disease Allogenic Animal Model Apoptosis Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD80 gene CD8B1 gene Cell Survival Cell surface Cells Cellular Metabolic Process Cellular biology Colon Conflict (Psychology)Development Disease model Environment Fluorescence Glycolysis Goals Hematologic Neoplasms Hematology Human Immune response Injections Interleukin-2 Kinetics Lead Light Liver Lymphoid Lymphoid Tissue Measures Mediating Memory Metabolic Mus Nature Outcome Oxidative Phosphorylation PD-1/PD-L1 Pathogenesis Pathway interactions Peripheral Blood Mononuclear Cell Play Predisposition Prevention Publications Regimen Regulatory T-Lymphocyte Relapse Reporting Resistance Role Serum Signal Transduction Spleen Stains T cell anergy T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Time Tissues Up-Regulation chronic graft versus host disease curative treatments design exhaustion graft vs host disease graft vs leukemia effect hematopoietic cell transplantation immune checkpoint immunoregulation insight leukemia leukemia/lymphoma metabolic profile novel preservation prevent programmed cell death ligand 1 programmed cell death protein 1 receptor side effect transplant model

项目摘要

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for relapsed hematological malignances (i.e. leukemia) due to graft-versus-leukemia (GVL) activity mediated by alloreactive T cells. However, alloreactive T cells also mediate graft-versus-host disease (GVHD), which remains the major obstacle for wide-spread application of allogeneic HCT. The long-term goal of our study is to develop novel regimens that prevent GVHD while preserving GVL activity. PD-L1 interacts with CD80 and PD-1. Although PD-L1/PD-1 regulation of immune responses plays an important role in animal models and humans, the role of PD-L1/CD80 remains largely unknown. Our recent publication in JCI has shed light on the importance of PD- L1/CD80 interactions. Our studies indicate that the outcome of PD-L1-mediated signaling in CD8+ T cells depends on the presence or absence of CD4+ T cells, the nature of the interacting receptors (i.e. CD80 versus PD-1) expressed by CD8+ T cells and the tissue environment (i.e. lymphoid versus parenchymal tissues) in which the signaling occurs. We observed that, in the absence of donor CD4+ T cells, CD8+ T-T interactions via PD-L1/CD80 augmented naïve/activating CD8+ T proliferation and survival in lymphoid tissues, leading to strong GVL activity. In contrast, host-tissue PD-L1 interactions with PD-1 and CD80 on CD8+ T cells in GVHD target tissues induced their proliferation and apoptosis, leading to prevention of GVHD. Donor CD4+ T cells helped CD8+ T cells via IL-2 become resistant against tissue PD-L1-mediated tolerance. Agonistic PD-L1-Ig binding to both CD80 and PD-1 augmented activated T cell proliferation and apoptosis. Conflicting results have been reported regarding the effects of glycolysis and oxidative phosphorylation (OXPHOS) in alloreactive T cells during the pathogenesis of acute GVHD. In kinetic studies, we observed that expression of CD80 and PD- 1 was associated with shift from glycolysis to OXPHOS. Therefore, we hypothesize that 1) PD-L1/CD80 and PD-L1/PD-1 interactions reciprocally regulate T cell glycolysis and OXPHOS, and the outcome depends on the tissue environment, due to differential T cell expression of CD80, PD-1, and PD-L1; 2) Reduction of serum IL-2 will increase the sensitivity of T cells towards tissue PD-L1-mediated or agonistic PD-L1- Ig-mediated tolerance in association with metabolic profile changes. The proposed studies will dissect the mechanisms by which PD-L1/CD80 interactions regulate glycolysis and OXPHOS in naïve/activating and activated T cells in lymphoid and GVHD target tissues (Aim 1). We will also design a regimen of sequentially administered anti-IL-2 and agonistic PD-L1-Ig to prevent GVHD and preserve strong GVL activity (Aim 2). These studies will reveal novel insights into T cell biology and GVHD pathogenesis and could lead to development of novel regimens that prevent GVHD while preserving GVL activity in humans. 1

同种异体造血细胞移植（HCT）是一种治愈性血液学的治疗疗法由于同种反应性T细胞介导的移植物 - 抗血清血症（GVL）活性引起的恶性肿瘤（即白血病）。然而，同种反应性T细胞还介导移植物抗宿主病（GVHD），这仍然是主要的广泛应用同种异体HCT的障碍。我们研究的长期目标是开发小说在保留GVL活性的同时预防GVHD的方案。 PD-L1与CD80和PD-1相互作用。虽然免疫调查的PD-L1/PD-1调节在动物模型和人类中起重要作用， PD-L1/CD80在很大程度上仍然未知。我们最近在JCI的出版物阐明了PD-的重要性 L1/CD80相互作用。我们的研究表明，CD8+ T细胞中PD-L1介导的信号传导的结果取决于CD4+ T细胞的存在或不存在，是相互作用接收器的性质（即CD80与 PD-1）由CD8+ T细胞和组织环境（即淋巴机与实质性定时）表示信号发生。我们观察到，在没有供体CD4+ T细胞的情况下，CD8+ T-T通过 PD-L1/CD80增强了幼稚/激活CD8+ T的增殖和淋巴组织中的存活，导致强大的GVL活性。相反，GVHD中的CD8+ T细胞上与PD-1和CD80的主机组织PD-L1相互作用目标时间诱导其增殖和凋亡，从而预防GVHD。供体CD4+ T细胞通过IL-2帮助CD8+ T细胞对组织PD-L1介导的耐受性具有抗性。激动剂PD-L1-Ig 与CD80和PD-1的结合增强了活化的T细胞增殖和凋亡。结果矛盾报道了糖酵解和氧化磷酸化（OXPHOS）对同种反应性T的影响急性GVHD发病机理期间的细胞。在动力学研究中，我们观察到CD80和PD-的表达 1与从糖酵解到Oxphos的转移有关。因此，我们假设1）PD-L1/CD80和 PD-L1/PD-1相互作用相互调节T细胞糖酵解和Oxphos，结果取决于在组织环境上，由于CD80，PD-1和PD-L1的T细胞表达差异； 2）还原血清IL-2的IL-2将增加T细胞对组织PD-L1介导或激动的PD-L1-的敏感性 IG介导的耐受性与代谢剖面变化有关。拟议的研究将剖析 PD-L1/CD80相互作用调节幼稚/激活中的糖酵解和Oxphos的机制激活的淋巴样和GVHD靶向时机中的T细胞（AIM 1）。我们还将依次设计一个方案施用抗IL-2和激动性PD-L1-Ig，以防止GVHD并保留强大的GVL活性（AIM 2）。这些研究将揭示对T细胞生物学和GVHD发病机理的新见解，并可能导致开发新型方案，可以预防GVHD，同时保留人类的GVL活性。 1