Shared pathway of WDFY4-dependent cross-presentation by cDC1 and cDC2 4535

Abstract Description Priming of CD8+ T cells against tumors or viral pathogens in vivo primarily depends on the cross-presentation of exogenous antigens by type 1 conventional dendritic cells (cDC1s). While cDC2 or monocyte-derived DCs have been shown to cross-present in vitro, the physiological relevance of these activities in vivo remains unclear. Inthis study, we utilized various genetic models to assess the role of different cDC subsets in presenting cell-associated and immune complexed antigens to CD4+ and CD8+ T cells in vivo. For cell-associated antigens, cDC1 were necessary and sufficient for in vivo priming of both CD4+ and CD8+ T cells. In contrast, for immune complex, either cDC1 or cDC2, but not monocytes or monocyte-derived cells, could carry out cross-presentation to CD8+ T cells in vivo, with cDC2 being superior to cDC1 for priming CD4+ T cells. Mice lacking cDC1s and vaccinated with antibody-tumor antigen immune complexes still could carry out cross-presentation to CD8+ T cells that was sufficient to mediate anti-tumor response. Notably, this cross-presentation was mediated by cDC2 and WDFY4-dependent, like cross-presentation of cell-associated antigens by cDC1, but unlike cross-presentation of soluble antigens. These results demonstrate previously unrecognized activity of WDFY4 in cDC2s and suggest a common pathway for receptor-mediated cross-presentation shared by cDC subsets. Funding Sources NIH R01AI150297, R01CA248919, R01AI162643 and R21AI163421 Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)