Using combination adjuvants to direct and control immune responses at the intestinal mucosa

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 DESCRIPTION (provided by applicant): Most pathogens enter the body at mucosal surfaces, yet, to date, the majority of licensed vaccines are injected parenterally, predominantly intramuscularly. While excellent at eliciting systemic immunity, they do not always induce the required mucosal immune responses. This highlights a gap in our understanding of how immunization may be manipulated to elicit mucosal immune responses and how such knowledge might be exploited to create better vaccines for mucosal pathogens. Defining the role that adjuvants play in this response is key to developing such vaccines; however, the mechanisms that dictate adjuvant driven mucosal antibody and cellular immune responses are not well understood. Our preliminary experiments using major histocompatibility complex class II (MHCII) tetramers to examine mucosal immune responses after intradermal immunization with a novel detoxified bacterial ADP- ribosylating enterotoxin, called dmLT, demonstrate that we can retarget the endogenous Th17 CD4 T cells and B cell IgA immune responses to the intestinal mucosa possibly by engagement of CD103+ skin dendritic cells. We also show intradermal immunization with dmLT plus a single CD4 T cell epitope can significantly reduce bacterial burden in a mouse model of Salmonella infection. These combined results, in addition to our past work, lead us to hypothesize that intradermal immunization with dmLT engages CD103+ dendritic cells, which prime antigen-specific B cells and CD4 T cells to upregulate gut- homing markers and mucosal trafficking. We further posit that when this is combined with adjuvants acting via different signaling pathways, both cellular and humoral immunity can be tuned to adapt to a mucosal pathogen of interest. We propose to: 1) assess antigen uptake and presentation when intradermal immunization with dmLT is combined with Th1 or Th2 driving adjuvants, determine how this immunization directs 2) T cells and 3) B cells to mucosal tissue, and 4) determine if this immunization is protective against a lethal enteric infection with Salmonella bacteria. This investigation should provide novel insights into how adjuvants regulate immunity at the mucosa and allow us to guide the response in favor of pathogen elimination.