Specific requirement of the p84/p110γ complex of PI3Kγ for antibody-activated, inducible cross-presentation in murine type 2 DCs

Cross-presentation by MHCI is optimally efficient in type 1 dendritic cells (DC) due to their high capacity for antigen processing. However, through specific pathways, other DCs, such as type 2 DCs and inflammatory DCs (iDCs) can also cross-present antigens. FcγR-mediated uptake by type 2 DC and iDC subsets mediates antibody-dependent cross-presentation and activation of CD8+ T cell responses. Here, we identify an important role for the p84 regulatory subunit of PI3Kγ in mediating efficient cross-presentation of exogenous antigens in otherwise inefficient cross-presenting cells, such as type 2 DCs and GM-CSF-derived iDCs. We show that FcγR-mediated cross-presentation on type 2 and iDCs depends on the enzymatic activity of the p84/p110γ complex of PI3Kγ, which controls the activity of the NADPH oxidase NOX2 and ROS production in murine spleen type 2 DCs and GM-CSF-derived iDCs. In contrast, p84/p110γ is largely dispensable for cross-presentation by type 1 DCs. These findings suggest that PI3Kγ-targeted therapies, currently considered for oncological practice, may interfere with the ability of type 2 DCs and iDCs to cross-present antigens contained in immune complexes. To investigate differential expression of genes in conventional dendritic cells, we performed bulk RNA sequencing in murine splenic WT type 1 and type 2 DCs. We also analysed murine splenic type 2 DCs from mice that are KO for each one of the regulatory subunits of PI3Kγ, p84 and p101. The dendritic cells were coming from mice either in steady state or euthanized 5 hours after intraperitoneal injections of Ova-anti Ova immune complexes.