Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, United States.
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, United States.
J Leukoc Biol. 2023 Jun 1;113(6):544-554. doi: 10.1093/jleuko/qiad010.
Aquaporins are a family of ubiquitously expressed transmembrane water channels implicated in a broad range of physiological functions. We have previously reported that aquaporin 4 (AQP4) is expressed on T cells and that treatment with a small molecule AQP4 inhibitor significantly delays T cell mediated heart allograft rejection. Using either genetic deletion or small molecule inhibitor, we show that AQP4 supports T cell receptor mediated activation of both mouse and human T cells. Intact AQP4 is required for optimal T cell receptor (TCR)-related signaling events, including nuclear translocation of transcription factors and phosphorylation of proximal TCR signaling molecules. AQP4 deficiency or inhibition impairs actin cytoskeleton rearrangements following TCR crosslinking, causing inferior TCR polarization and a loss of TCR signaling. Our findings reveal a novel function of AQP4 in T lymphocytes and identify AQP4 as a potential therapeutic target for preventing TCR-mediated T cell activation.
水通道蛋白是一类广泛表达的跨膜水分子通道，与多种生理功能有关。我们之前的研究表明，水通道蛋白 4（AQP4）在 T 细胞上表达，并且小分子 AQP4 抑制剂的治疗可以显著延迟 T 细胞介导的心脏同种异体移植物排斥反应。通过基因敲除或小分子抑制剂，我们发现 AQP4 支持小鼠和人 T 细胞的 T 细胞受体（TCR）介导的激活。完整的 AQP4 是最佳 TCR 相关信号事件所必需的，包括转录因子的核易位和 TCR 信号分子的近端磷酸化。AQP4 缺乏或抑制会破坏 TCR 交联后的肌动蛋白细胞骨架重排，导致 TCR 极化不良和 TCR 信号丢失。我们的研究结果揭示了 AQP4 在 T 淋巴细胞中的新功能，并将 AQP4 鉴定为预防 TCR 介导的 T 细胞激活的潜在治疗靶点。
