Investigating the role of type 1 interferon signaling on vaccine stability within lymphatic endothelial cells

PROJECT SUMMARY/ABSTRACT: Lymphatic endothelial cells (LECs) act as the first point of contact for antigen and immune cells entering the lymph node (LN) via lymphatic vessels. LECs comprise the subcapsular sinus as well as medullary/cortical structures of the LN. These cells, however, play more than a structural role. Antigen acquired by LECs following protein subunit immunization or viral infection is retained six weeks or more and is actively transferred to dendritic cells for presentation to memory CD8+ T cells. This process of antigen archiving and exchange enhances CD8+ T cell function and local protective immunity. While this process of “antigen archiving” is well supported, little is known regarding the molecular pathways activated at the time of vaccination that facilitate archiving in LECs. Furthermore, the capacity of these cells to retain material from mRNA vaccines has not been evaluated A core requirement for antigen archiving is the presence of an innate stimulus. Adjuvants that induce antigen archiving rely in part or entirely on stimulation of virus-sensing toll-like receptors (TLRs) which lead to rapid type 1 interferon production in the LN. Furthermore, the degree of antigen persistence is dose-dependent on quantity of TLR agonist. Based on our preliminary findings, we hypothesize that protein and RNA delivered by protein subunit or mRNA vaccination persists for longer periods in LECs that have been stimulated by type 1 IFN. Our aims are as follows: (1) Determine if type 1 IFN response in LECs promotes antigen archiving and enhances protective immunity and (2) Determine how type 1 IFN signaling within LECs regulates vaccine RNA stability and downstream protective immunity. These aims are significant because they will lead to an understanding of stimuli that can prolong mRNA vaccine and protein subunit vaccine half-life in the LN and enhance T cell mediated immunity, which is relevant to vaccine adjuvant design.