Physical Sciences, Sunnybrook Research Institute, Toronto, Canada.
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada.
Sci Rep. 2023 Mar 21;13(1):4609. doi: 10.1038/s41598-023-30999-w.
PVR (poliovirus receptor) functions as a ligand that signals through TIGIT and CD96 to induce suppression of T-cell and NK-cell responses. Alternatively, PVR binds to CD226, resulting in a co-stimulatory signal. To date, TIGIT antibody antagonists have been developed to restore immune functions and allow PVR to signal though CD226 in the context of cancer immunotherapy. Due to PVR receptor heterogeneity, agonizing either of these pathways with a recombinant form of the PVR extracellular domain represents a therapeutic strategy for either immunosuppression or activation. Here, we developed a minimal murine PVR-Fc fusion construct, consisting of only the IgV domain of PVR (vdPVR-Fc), and assessed its ability to dampen inflammatory responses in a murine model of psoriasis. vdPVR-Fc and PVR-Fc containing the full-length extracellular domain bound to TIGIT, CD96 and CD226 with similar low nanomolar affinities as defined by surface plasmon resonance. vdPVR-Fc was also able to suppress the in-vitro proliferation of murine CD4 and CD8 T-cells in mixed splenocyte cultures. Importantly, vdPVR-Fc delayed the onset, and reduced inflammatory responses (scaling and thickness) in a murine model of psoriasis. Collectively, our results suggest that the minimal IgV domain of PVR is sufficient to dampen immune responses in-vitro and attenuate symptoms of psoriasis in-vivo.
PVR（脊髓灰质炎病毒受体）作为一种配体发挥作用，通过 TIGIT 和 CD96 发出信号，从而抑制 T 细胞和 NK 细胞的反应。或者，PVR 与 CD226 结合，产生共刺激信号。迄今为止，已经开发出 TIGIT 抗体拮抗剂来恢复免疫功能，并允许 PVR 在癌症免疫治疗的背景下通过 CD226 发出信号。由于 PVR 受体的异质性，用 PVR 细胞外结构域的重组形式激动这些途径中的任何一种，代表了一种免疫抑制或激活的治疗策略。在这里，我们开发了一种最小的小鼠 PVR-Fc 融合构建体，仅由 PVR 的 IgV 结构域组成（vdPVR-Fc），并评估了其在银屑病小鼠模型中抑制炎症反应的能力。vdPVR-Fc 和含有全长细胞外结构域的 PVR-Fc 与 TIGIT、CD96 和 CD226 结合的亲和力相似，均为低纳摩尔亲和力，如表面等离子体共振所定义。vdPVR-Fc 还能够抑制混合脾细胞培养中体外小鼠 CD4 和 CD8 T 细胞的增殖。重要的是，vdPVR-Fc 延迟了银屑病小鼠模型的发病，并减轻了炎症反应（评分和厚度）。总的来说，我们的结果表明，PVR 的最小 IgV 结构域足以在体外抑制免疫反应，并在体内减轻银屑病的症状。
