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

Abstract

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.

• Authors: Yipeng Zhao, Wei Qiu, Junchen Liu, Xiaolu Yuan, Wenqian Mao, Jun Yin, BiWen Peng, WanHong Liu, Song Han, XiaoHua He
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 34 Issue 11 Pg. 15492-15503 (11 2020) ISSN: 1530-6860 [Electronic] United States
• PMID: 32981181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Chemical References

• Kv1.3 Potassium Channel
• Potassium Channel Blockers
• Programmed Cell Death 1 Receptor
• Positive Regulatory Domain I-Binding Factor 1

Topics

• Animals
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Encephalomyelitis, Autoimmune, Experimental (etiology, metabolism, pathology, prevention & control)
• Gene Expression Regulation
• Inflammation (etiology, metabolism, pathology, prevention & control)
• Kv1.3 Potassium Channel (antagonists & inhibitors)
• Male
• Neurons (drug effects, immunology, metabolism, pathology)
• Positive Regulatory Domain I-Binding Factor 1 (genetics, metabolism)
• Potassium Channel Blockers (pharmacology)
• Programmed Cell Death 1 Receptor (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction