Shared pathway of WDFY4-dependent cross-presentation of immune complexes by cDC1 and cDC2

Priming CD8⁺ T cells against tumors or viral pathogens results largely from cross-presentation of exogenous antigens by type 1 conventional dendritic cells (cDC1s). Although monocyte-derived DCs and cDC2s can cross-present in vitro, their physiological relevance remains unclear. Here, we used genetic models to evaluate the role of cDC subsets in presentation of cell-associated and immune complex antigens to CD4⁺ and CD8⁺ T cells in vivo. For cell-associated antigens, cDC1s were necessary and sufficient to prime both CD4⁺ and CD8⁺ T cells. In contrast, for immune complex antigens, either cDC1 or cDC2, but not monocyte-derived DCs, could carry out cross-presentation to CD8⁺ T cells. Mice lacking cDC1 and vaccinated with immune complexes could cross-prime CD8⁺ T cells that were sufficient to mediate tumor rejection. Notably, this cross-presentation mediated by cDC2 was also WDFY4 dependent, similar to cross-presentation of cell-associated antigens by cDC1. These results demonstrate a previously unrecognized activity of WDFY4 in cDC2s and suggest a cross-presentation pathway shared by cDC subsets.