Abstract EN:

Insulin-regulated aminopeptidase (IRAP) localizes to storage-type endosomes in many non-immune and immune cell types. In dendritic cells (DCs), IRAP functions as trimming peptidase to generate peptide ligands for MHC class I molecules (MHC-I). Absence of IRAP led to a defect in the presentation of internalized antigen on MHC-I (referred to as cross-presentation) in vitro and in vivo. Importantly, IRAP was not required for the “classical” presentation pathways (i. E. Presentation of extracellular antigens on MHC-II as well as presentation of intracellular antigens on MHC-I). Further supported by the colocalization and physical interaction of MHC-I with IRAP, these observations suggest that IRAP marks a cross-presentation compartment in which final trimming and loading on MHC-I can take place. We show that this compartment, marked by STX6 and Rab14, is functional in both CD8+ and CD8- DC subsets. In DCs, upon antigen internalization, IRAP vesicles are rapidly recruited to the phagosome. Additional to its function in antigen trimming, IRAP seems to regulate phagosome dynamics. In IRAP-deficient cells, phagosome maturation was accelerated, as shown by the rapid acquirement of late endosomal and lysosomal markers to the phagosome and increased antigen degradation. Thus, IRAP endosomes have at least two important roles in the DCs physiology: the trimming of antigenic peptides and the delay of phagosome maturation that is beneficial for cross-presentation. Understanding the stimuli that regulate IRAP mobilization, and possibly cross-presentation, could be relevant in order to understand if and how DCs control their different functions, including antigen presentation.