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

异基因造血细胞移植（HCT）是治疗复发性血液病的一种有效方法。 由于同种异体反应性T细胞介导的移植物抗白血病（GVL）活性引起的恶性肿瘤（即白血病）。 然而，同种异体反应性T细胞也介导移植物抗宿主病（GVHD），其仍然是主要的免疫缺陷病毒。 阻碍了异基因HCT的广泛应用。我们研究的长期目标是开发新颖的 预防GVHD同时保留GVL活性的方案。PD-L1与CD 80和PD-1相互作用。虽然 PD-L1/PD-1调节免疫应答在动物模型和人类中起着重要作用， PD-L1/CD 80在很大程度上仍然未知。我们最近在JCI上发表的文章阐明了PD的重要性- L1/CD 80相互作用。我们的研究表明，CD 8 + T细胞中PD-L1介导的信号转导的结果 取决于CD 4 + T细胞的存在或不存在、相互作用受体的性质（即CD 80相对于 PD-1）和组织环境（即淋巴组织与实质组织）的差异。 信号发生的时间。我们观察到，在缺乏供体CD 4 + T细胞的情况下，CD 8 + T-T相互作用通过 PD-L1/CD 80增强淋巴组织中幼稚/活化CD 8 + T细胞增殖和存活，导致 强GVL活性。相反，在GVHD中，宿主组织PD-L1与PD-1和CD 8 + T细胞上的CD 80的相互作用 靶组织诱导其增殖和凋亡，导致GVHD的预防。供体CD 4 + T细胞 通过IL-2帮助CD 8 + T细胞抵抗组织PD-L1介导的耐受。激动剂PD-L1-IG 与CD 80和PD-1两者的结合增强了活化的T细胞增殖和凋亡。测试结果显示， 关于糖酵解和氧化磷酸化（OXPHOS）在同种异体反应性T细胞中的作用， 急性GVHD发病过程中的细胞。在动力学研究中，我们观察到CD 80和PD-1的表达， 1与糖酵解向OXPHOS的转变有关。因此，我们假设1）PD-L1/CD 80和 PD-L1/PD-1相互作用可调节T细胞糖酵解和OXPHOS，结果取决于 由于CD 80、PD-1和PD-L1的不同T细胞表达，对组织环境的影响; 2）减少 的血清IL-2将增加T细胞对组织PD-L1介导的或激动性PD-L1的敏感性。 免疫球蛋白介导的耐受性与代谢谱变化相关。拟议的研究将剖析 PD-L1/CD 80相互作用调节糖酵解和OXPHOS的机制， 淋巴和GVHD靶组织中的活化T细胞（Aim 1）。我们还将设计一个方案， 施用抗IL-2和激动性PD-L1-IG Ig以预防GVHD和保持强GVL活性（目的2）。 这些研究将揭示T细胞生物学和GVHD发病机制的新见解，并可能导致 开发预防GVHD同时保留人类GVL活性的新方案。 1

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