Differential uptake and cross-presentation of soluble and necrotic cell antigen by human DC subsets

Cross-presentation is the mechanism by which exogenous Ag is processed for recognition by CD8 ⁺ T cells. Murine CD8α ⁺ DCs are specialized at cross-presenting soluble and cellular Ag, but in humans this process is poorly characterized. In this study, we examined uptake and cross-presentation of soluble and cellular Ag by human blood CD141 ⁺ DCs, the human equivalent of mouse CD8α ⁺ DCs, and compared them with human monocyte-derived DCs (MoDCs) and blood CD1c ⁺ DC subsets. MoDCs were superior in their capacity to internalize and cross-present soluble protein whereas CD141 ⁺ DCs were more efficient at ingesting and cross-presenting cellular Ag. Whilst cross-presentation by CD1c ⁺ DCs and CD141 ⁺ DCs was dependent on the proteasome, and hence cytosolic translocation, cross-presentation by MoDCs was not. Inhibition of endosomal acidification enhanced cross-presentation by CD1c ⁺ DCs and MoDCs but not by CD141 ⁺ DCs. These data demonstrate that CD1c ⁺ DCs, CD141 ⁺ DCs, and MoDCs are capable of cross-presentation; however, they do so via different mechanisms. Moreover, they demonstrate that human CD141 ⁺ DCs, like their murine CD8α ⁺ DC counterparts, are specialized at cross-presenting cellular Ag, most likely mediated by an enhanced capacity to ingest cellular Ag combined with subtle changes in lysosomal pH during Ag processing and use of the cytosolic pathway.