CONICET | Buscador de Institutos y Recursos Humanos

Cross-presentation by MHC-I molecules allows the detection of exogenous antigens by CD8+ T lymphocytes. This process is crucial to initiate cytotoxic immune responses against many pathogens (i.e. Toxoplasma gondii) and tumors. To achieve efficient cross-presentation, dendritic cells (DCs) have developed distinctive specializations of their endocytic pathway, such as as limited proteolytic activity in phagosomes and endosomes or the recruitment of endoplasmic reticulum (ER) components to these compartments. Lately, we have focused our study in understanding the modulation of MHC-I intracellular transport in DCs and we have identified the small GTPase Rab22a as a key regulator of this process. In this sense, we have shown that Rab22a controls MHC-I trafficking and antigen cross presentation by DCs. Our results demonstrate that Rab22a is recruited to DC endosomes and phagosomes, as well as to the vacuole containing T. gondii parasites. The silencing of Rab22a expression did not affect the uptake of exogenous antigens or parasite invasion, but it drastically reduced the intracellular pool and the recycling of MHC-I molecules. The knockdown of Rab22a also hampered the cross-presentation of soluble, particulate and T. gondii associated antigens, but not the endogenous MHC-I antigen presentation through the classical secretory pathway. Furthermore, Rab22a KD DCs evidenced a significant impairment in the recruitment of ER-derived proteins to endosomes (but not to phagosomes) and a marked deficiency in endosomal maturation. Our findings provide compelling evidence that Rab22a plays a central role in the MHC-I endocytic trafficking and other relevant intracellular events that guarantee an efficient crosspresentation by DCs. Currently, other molecular effectors of the endocytic pathway with potential implications in antigen cross-presentation are being investigated by our group.