Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype

作者：Chimote Ameet A; Hajdu Peter; Kottyan Leah C; Harley John B; Yun Yeoheung; Conforti Laura

来源：Journal of Autoimmunity, 2016, 69: 86-93.

DOI：10.1016/j.jaut.2016.03.004

• Autoimmunity
• T cell
• Kv1.3 ion channel
• CD40 ligand
• Lipid nanoparticles
• Ca2+ signaling

Ca2+ signaling controls activation and effector functions of T lymphocytes. Ca2+ levels also regulate NFAT activation and CD40 ligand (CD40L) expression in T cells. CD40L in activated memory T cells binds to its cognate receptor, CD40, on other cell types resulting in the production of antibodies and pro inflammatory mediators. The CD40L/CD40 interaction is implicated in the pathogenesis of autoimmune disorders and CD40L is widely recognized as a therapeutic target. Ca2+ signaling in T cells is regulated by Kv1.3 channels. We have developed lipid nanoparticles that deliver Kv1.3 siRNAs (Kv1.3-NPs) selectively to CD45RO(+) memory T cells and reduce the activation-induced Ca2+ influx. Herein we report that Kv1.3-NPs reduced NFAT activation and CD40L expression exclusively in CD45RO(+) T cells. Furthermore, Kv1.3-NPs suppressed cytokine release and induced a phenotype switch of T cells from predominantly memory to naive. These findings indicate that Kv1.3-NPs operate as targeted immune suppressive agents with promising therapeutic potentials.

• 出版日期2016-5