Toll-like receptor control of endocytic antigen cross-presentation

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PROPOSAL SUMMARY There are critical vaccine barriers to eliciting cytotoxic CD8 T cells against intracellular pathogens. Current vaccine technologies have yielded limited success for protection against infections with intracellular pathogens like tuberculosis, malaria, and HIV where CD8 T cells prevent and control infection. Licensed vaccines generate mostly neutralizing or opsonizing antibodies, and their efficacy is contingent on a stable antigenic profile. Some adjuvants like alum elicit helper type 2 CD4 T cells, but CD8 T cell immunity has been difficult to achieve. CD8 T cells can target conserved internal microbial components that are more difficult for pathogens to mutate. The unparalleled potency, cross-protective immunity, and immunological memory mediated by CD8 T cells underscores the urgency of developing CD8 T cell vaccines. To elicit CD8 T cell immunity, an adjuvant needs to induce MHC presentation of the antigens present in the vaccine formulation by dendritic cells (DC), potent antigen-presenting cells that prime naïve CD8 T cells. The MHC class I presentation of exogenous antigens such as vaccine components by DC takes place through cross-presentation. Understanding the mechanisms that regulate DC cross-presentation is thus critical for designing adjuvants that elicit strong CD8 T cell immunity. Our published and unpublished work has shown that Toll-like receptors (TLR), which detect microbes and alert the immune system, positively regulate DC cross-presentation. When studying the regulation of cross-presentation, it is important to consider the route of antigen internalization into DC. Depending on the size of the internalized antigen, internalization can be through phagocytosis (for particles that are >1µm in diameter) or endocytosis (<1µm in diameter). We found that the TLR-dependent regulation of cross-presentation is different for endocytic and phagocytic antigens. The common component that dictates the efficiency of cross-presentation to CD8 T cells is correct subcellular trafficking of MHC-I molecules to sites of internalized antigen. For phagocytic antigens, TLR signals control the traffic of MHC-I molecules from endosomal recycling compartments (ERC) in DC specifically to phagocytic antigens such as from bacteria or infected dying cells. For endocytic antigens, we found that a distinct TLR signaling machinery is involved, which controls endocytic antigen cross-presentation to CD8 T cells and traffics MHC-I molecules to endocytosed antigen from a cellular source other than the ERC. Using a variety of validated and complementary approaches, we will investigate TLR-regulated mechanisms of endocytic antigen cross-presentation and subcellular MHC-I trafficking to endocytosed antigens. We will elucidate how the distinct TLR mechanisms that regulate endocytic antigen cross-presentation impact protective circulating and tissue-resident CD8 T cell memory elicited by vaccination. We will use prototype subunit vaccines formulated with adjuvant/TLR ligand combinations that engage and boost DC endocytic antigen cross-presentation. Deciphering regulatory mechanisms of endocytic antigen cross-presentation will directly impact the design of effective CD8 T cell vaccines to clinically relevant old and new pathogens including those with pandemic potential.