Keynote Lecture 1A non-canonical pathway of cross-presentation disables self/non-self discrimination

Abstract

The classic pathway of MHC class I (MHC-I) presentation by dendritic cells (DC) is critical to initiate immunity against microbial pathogens. For viruses that do not infect DC or when the antigen presentation functions of infected DC have been compromised, cross-presentation ensures the mobilization of an antiviral CD8 T cell response. Cross-presentation is an adaptation of the classical pathway of MHC-I presentation that DC specialize in to present peptides derived from extracellular antigens by MHC-I molecules. Understanding the mechanisms and regulation of cross-presentation has direct implications to the urgent need for developing T cell vaccines against intracellular pathogens such as HIV, Mycobacterium tuberculosis and malaria. We have shown that the cross-presentation of particulate antigens is highly dependent on Toll-like receptor (TLR) signaling in phagosomes. We reported that MHC-I molecules accumulate in endosomal recycling compartments (ERC) in DC and serve to supply phagosomes with MHC-I molecules for loading with peptides during cross-presentation. Mechanistically, MyD88-dependent TLR signals drive IκB-kinase (IKK)2-mediated phosphorylation of phagosome-associated synaptosome associated protein 23 (SNAP23). Phospho-SNAP23 stabilizes SNARE complexes between the ERC and phagosomes and orchestrates their fusion. As a result, ERC-resident MHC-I molecules are delivered specifically to phagosomes containing TLR ligands favoring the cross-presentation of microbial over self peptides. I will review this pathway and present unpublished data showing how subcellular mislocalization of MHC-I molecules under specific circumstances disrupts the TLR-mediated control of cross-presentation and disables the ability to discriminate self from non-self peptides.