Fc gamma receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3(+) dendritic cells

The reactivation of human cytomegalovirus (HCMV) poses a serious health threat to immune compromised individuals. As a treatment strategy, dendritic cell (DC) vaccination trials are ongoing. Recent work suggests that BDCA-3(+) (CD141(+)) subset DCs may be particularly effective in DC vaccination trials. BDCA-3(+) DCs had however been mostly characterized for their ability to cross-present antigen from necrotic cells. We here describe our study of human BDCA-3(+) DCs in elicitation of HCMV-specific CD8(+) T-cell clones. We show that Fcgamma-receptor (Fc gamma R) antigen targeting facilitates antigen cross-presentation in several DC subsets, including BDCA-3(+) DCs. Fc gamma R antigen targeting stimulates antigen uptake by BDCA-1(+) rather than BDCA-3(+) DCs. Conversely, BDCA-3(+) DCs and not BDCA-1(+) DCs show improved cross-presentation by Fc gamma R targeting, as measured by induced release of IFN gamma and TNF by antigen-specific CD8(+) T cells. Fc gamma R-facilitated cross-presentation requires antigen processing in both an acidic endosomal compartment and by the proteasome, and did not induce substantial DC maturation. Fc gamma RII is the most abundantly expressed Fc gamma R on both BDCA-1(+) and BDCA-3(+) DCs. Furthermore we show that BDCA-3(+) DCs express relatively more stimulatory Fc gamma RIIa than inhibitory Fc gamma RIIb in comparison with BDCA-1(+) DCs. These studies support the exploration of Fc gamma R antigen targeting to BDCA-3(+) DCs for human vaccination purposes. (Blood. 2012; 120(26): 5163-5172)