Resting and Activated DCs Present Exogenous Antigens to CD4 T Cells by Distinct Antigen Processing Pathways

Abstract

Activation of immature DCs by pathogens results in an APC that is a highly efficient stimulator of naïve CD4 T cells. Curiously, even fully-mature DCs can efficiently process and present antigenic peptide to CD4 T cells, however the mechanism used by mature DCs to function as APCs and whether these mechanisms are identical in immature DC and mature DC is not known. We now show that that immature and mature DCs differ use different mechanisms to present distinct epitopes of the influenza virus hemagglutinin (HA) protein to T cells. Immature DCs use newly-synthesized MHC-II targeted to DM+ late endosomal antigen processing compartments for presentation to HA-specific T cells. By contrast, mature DCs use recycling MHC-II that enters Rab11a+ early endosomes to process and present a distinct HA epitope to different HA-specific T cells. Rab11a knock-down inhibits recycling of pMHC-II and inhibits presentation of a “recycling endosome” epitope of HA from influenza virus internalized in mature DCs. These studies highlight a “division of labor” in DCs in which immature DCs preferentially present antigens acquired in late endosomes on MHC-II but mature DCs use recycling pMHC-II to efficiently present antigenic peptides acquired in early endosomes for CD4 T cell activation.