The voltage-gated Kv1.3 K+ channel in effector memory T cells (TEM) serves as a new therapeutic target for multiple sclerosis (MS).In our previous studies, the novel peptide ADWX-1 was designed and synthesized as a specific Kv1.3 blocker, and this peptide exhibited high potency and selectivity toward Kv1.3 over the related Kv1.1 and Kv 1.2 channels.However, it is unclear if and how ADWX-1 alleviates experimental autoimmune encephalomyelitis (EAE), a model for MS.In this study, the administration of ADWX-1 significantly ameliorated the rat EAE model by selectively inhibiting CCR7-phenotype TEM cell activation.Interestingly, ADWX-1, a selective modulator of TEM cell activation, preferentially inhibited the activation of effector CD4+CCR7-cells through regulating both IL-2 signaling and the expression of Kv 1.3.In contrast,the Kv1.3-specific peptide had little effect on na(i)ve and memory CD4+CCR7+ cells, therefore limiting side effects.Furthermore, we determined that ADWX-1 is involved in the regulation of NF-κB signaling through upstream protein kinase C-θ (PKCθ) in the IL-2 pathway of CD4+CCR7-cells.The elevated expression of Kv1.3 mRNA and protein in activated CD4+CCR7-cells was reduced by ADWX-1 engagement; however, an apparent alteration in CD4+CCR7+ cells was not observed.