# PD-L1 interacts with CD80 and PD-1 to regulate GVHD and GVL activity > **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $395,946 ## Abstract 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 ## Key facts - **NIH application ID:** 9857573 - **Project number:** 5R01CA228465-03 - **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE - **Principal Investigator:** Defu Zeng - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $395,946 - **Award type:** 5 - **Project period:** 2018-03-01 → 2023-02-28 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9857573 ## Citation > US National Institutes of Health, RePORTER application 9857573, PD-L1 interacts with CD80 and PD-1 to regulate GVHD and GVL activity (5R01CA228465-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9857573. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*