Blockade of Kv1.3 potassium channel inhibits CD8+ T cell‐mediated neuroinflammation via PD‐1/Blimp‐1 signaling

• Published in: The FASEB journal Vol. 34; no. 11; pp. 15492 - 15503
• Main Authors: Zhao, Yipeng, Qiu, Wei, Liu, Junchen, Yuan, Xiaolu, Mao, Wenqian, Yin, Jun, Peng, BiWen, Liu, WanHong, Han, Song, He, XiaoHua
• Format: Journal Article
• Language: English
• Published: United States 01.11.2020
• Subjects: Animals; Blimp‐1; CD8+ T cells; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; EAE; Encephalomyelitis, Autoimmune, Experimental - etiology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Gene Expression Regulation; Inflammation - etiology; Inflammation - metabolism; Inflammation - pathology; Inflammation - prevention & control; Kv1.3 channel; Kv1.3 Potassium Channel - antagonists & inhibitors; Male; Neurons - drug effects; Neurons - immunology; Neurons - metabolism; Neurons - pathology; PD‐1; Positive Regulatory Domain I-Binding Factor 1 - genetics; Positive Regulatory Domain I-Binding Factor 1 - metabolism; Potassium Channel Blockers - pharmacology; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction; EAE; CD8+ T cells; PD-1; Kv1.3 channel; Blimp-1
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202000861RR

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.