Enhancement of antigen-specific responses following protein vaccination by Albumin- Flt3L expanded dendritic cells: Potential implications

Abstract

Abstract Due to the crucial role that dendritic cells (DCs) play in uptaking antigens following vaccination and cross presenting these antigens for the activation of antigen-specific immunity, a strategy that can induce potent expansion and activation of cross-presenting DCs may serve as a potential strategy to enhance the efficacy of therapeutic and prophylactic vaccinations. Flt3L is a cytokine known to expand cross-presenting DCs, but is limited by its global distribution and short half-life in vivo. To overcome these shortcomings, we generated a novel immunostimulatory molecule by fusing Flt3L to Albumin; a protein known for its long half-life and trafficking to lymph nodes. Our results revealed that Albumin-Flt3L (Alb-Flt3L) retains Flt3L’s endogenous capabilities to increase total CD11c+MHCII+, CD11c+MHCII+B220+SiglecH+, and CD11c+MHCII+CD8a+ DC populations in vitro, and in vivo following a single injection, compared to Flt3L. Our data also demonstrates that following vaccination with whole Ovalbumin protein (OVA), Alb-Flt3L treated mice saw an increase in antigen-specific immunity, measured by OVA-tetramer-positive CD8+ T cells, CD4+ and CD8+ cells producing IFN-g following ex vivo restimulation, and serum OVA specific IgG2a. When vaccinated with HPV-associated antigen E7 as a long peptide that requires uptake and cross-presentation to effectively load on MHCI and subsequently activate CD8+ T cells, E7-specific T cell populations significantly increased in Alb-Flt3L treated mice compared to controls. Further investigation is underway to study the ability of Alb-Flt3L to enhance vaccination induced immune responses as well as to study the mechanism by which these phenomena occur.