A Novel Vaccine Strategy for Promoting T cell Function by Boosting Dendritic Cells

Lipid-nanoparticle (LNP)-based vaccine technology has a critical limitation: LNPs lack specificity in targeting antigen-presenting cells within lymph nodes, resulting in their widespread distribution throughout the body, including unintended infiltration into organs and cells.

This proposal addresses this challenge by precisely directing LNPs to the pattern recognition receptor dectin-1 on professional antigen-presenting cells, particularly dendritic cells.

Our groundbreaking discovery reveals that bacterial proteins can activate dectin-1, that originally is designed to recognize beta-glucan derivatives from fungi. Our strategy involves fusing bacterial proteins with LNPs carrying mRNA for diverse antigens.

Subsequent uptake of LNPs via dectin-1 will lead to the production of protein antigens in dendritic cells, facilitating their presentation to cytotoxic T cells through the major histocompatibility complex (MHC) class I pathway.

This process triggers a clonal expansion of cytotoxic T cells, resulting in a considerably more effective and direct immune response compared to current vaccine modalities. We plan to continue examining proteins and specific peptide sequences that exhibit affinity for dectin-1. The capacity of bacterial proteins and their peptides to augment T cell activity will be investigated.

Our approach has the potential to enhance cytotoxic T cell immune responses against microbes, both bacteria and viruses such as human papillomavirus (HPV) and SARS-CoV-2.