Kv1.3 potassium channel is considered as a target for the treatment of autoimmune diseases such as multiple sclerosis (MS), since Kv1.3 blockade suppresses memory T cell activation including cytotoxic CD8+ T cells. However, the underlying signaling pathway related to autoimmune CD8+ T cell inhibition by Kv1.3 channel in neuroinflammatory diseases remains unclear. We found that ImK, a selective Kv1.3 blocker, reduced auto‐reactive CD8+ T cell infiltration in the spinal cords of experimental autoimmune encephalomyelitis (EAE) rats, an animal model of MS. ImK suppressed transcriptional factor Blimp‐1 expression and reduced the cytotoxicity of CD8+ T cells on neuronal cells. Furthermore, ImK upregulated co‐inhibitory molecule PD‐1 to inhibit B lymphocyte‐induced maturation protein (Blimp‐1) in an IL‐2 independent way. In addition, PD‐1 inhibitor impaired the suppression of ImK on CD8+ T cells and accelerated EAE progression. Our study demonstrated a novel regulatory mechanism of Kv1.3 blockade on modulating CD8+ T cell differentiation through PD‐1/Blimp‐1 signaling. This work expands the understanding of Kv1.3 channel for modulating neuroinflammation.

中文翻译：

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阻断 Kv1.3 钾通道通过 PD-1/Blimp-1 信号传导抑制 CD8+T 细胞介导的神经炎症

Kv1.3 钾通道被认为是治疗多发性硬化症 (MS) 等自身免疫性疾病的靶点，因为 Kv1.3 阻断抑制记忆 T 细胞活化，包括细胞毒性 CD8+ T 细胞。然而，与 Kv1.3 通道在神经炎症性疾病中抑制自身免疫性 CD8+ T 细胞相关的潜在信号通路仍不清楚。我们发现 ImK 是一种选择性 Kv1.3 阻滞剂，可减少实验性自身免疫性脑脊髓炎 (EAE) 大鼠（一种 MS 动物模型）脊髓中的自身反应性 CD8+ T 细胞浸润。ImK 抑制转录因子 Blimp-1 表达并降低 CD8+ T 细胞对神经元细胞的细胞毒性。此外，ImK 上调共抑制分子 PD-1，以独立于 IL-2 的方式抑制 B 淋巴细胞诱导的成熟蛋白 (Blimp-1)。此外，PD-1 抑制剂削弱了对 CD8+ T 细胞的 ImK 抑制并加速了 EAE 进展。我们的研究证明了 Kv1.3 阻断通过 PD-1/Blimp-1 信号传导调节 CD8+ T 细胞分化的新调节机制。这项工作扩展了对 Kv1.3 通道调节神经炎症的理解。