title: Nanovesicle-targeted Kv1.3 knockdown in memory T cells suppresses CD40L expression and memory phenotype.
abstract: Ca(2+) signaling controls activation and effector functions of T lymphocytes. Ca(2+) 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. Ca(2+) 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 Ca(2+) 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 naïve. These findings indicate that Kv1.3-NPs operate as targeted immune suppressive agents with promising therapeutic potentials.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Ameet A
authors.initials: AA
authors.lastname: Chimote
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hajdu
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Kottyan
authors.affiliation: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA; US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: North Carolina A & T State University, Chemical, Biological and Bioengineering Department, Greensboro, NC, USA.
authors.forename: Yeoheung
authors.initials: Y
authors.lastname: Yun
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Cincinnati, Cincinnati, OH, USA. Electronic address: Laura.Conforti@uc.edu.
authors.forename: Laura
authors.initials: L
authors.lastname: Conforti
mesh_terms: D000328:Adult; D000954:Antigens, Surface / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D051664:Kv1.3 Potassium Channel / Q000235:genetics*; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000378:metabolism; D053758:Nanoparticles; D010641:Phenotype; D021381:Protein Transport; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000954:Antigens, Surface; D016207:Cytokines; D051664:Kv1.3 Potassium Channel; D050778:NFATC Transcription Factors; D023201:CD40 Ligand
keywords: Autoimmunity; CD40 ligand; Ca(2+) signaling; Kv1.3 ion channel; Lipid nanoparticles; T cell