Altering the endocytic network to understand antigen cross-presentation

IGNACIO CEBRIÁN

Mendoza

Workshop; Membrane trafficking in cell plasticity and defense mechanisms; 2018

Área de Química Biológica, Facultad de Ciencias Médicas, UNCuyo

Cross-presentation by MHC class I molecules allows the detection of exogenous antigens by CD8+ T lymphocytes. This process is determinant to initiate cytotoxic immune responses against many pathogens (i.e. Toxoplasma gondii) and tumors. To achieve efficient cross-presentation, dendritic cells (DCs) have developed highly specialized adaptations of their endocytic network. Consequently, DCs are the most potent antigen presenting cell type to accomplish this immunological process. However, a complete view of the many molecular effectors involved in antigen cross-presentation is still missing. We have recently shown that the small GTPase Rab22a regulates the transport of MHC-I in DCs by stabilizing the intracellular pool of these molecules at the recycling center, allowing the normal delivery to phagosomes and guaranteeing an efficient recycling to the cell surface. Furthermore, we demonstrated that Rab22a modulates the acquisition of ER-derived proteins to endosomes but not to phagosomes in DCs. All these intracellular trafficking defects that take place in Rab22a deficient DCs drive to a significant impairment of antigen cross-presentation, including soluble, particulate and T. gondii-associated antigens. Recently, we have also started to study the role of sorting nexin (SNX) proteins during antigen cross-presentation. SNXs are characterized by the presence of a phox-homology domain that interacts with elements of the endocytic pathway enriched with phosphatidylinositol-3-monophosphate. In this way, SNXs control key features of endocytosis, as well as endosomal signaling, sorting and tubulation. In particular, SNX17 associates with compartments of the early endocytic network and participates in several processes of intracellular recycling. We have identified SNX17 as a main regulator of antigen internalization and cross-presentation by DCs. Our findings provide compelling evidence that Rab22a and SNX17 play central roles in the endocytic transport of DCs and are crucial molecules to guarantee an efficient antigen cross presentation.