Specific Requirement of the p84/p110γ Complex of PI3Kγ for Antibody-Activated, Inducible Cross-Presentation in Murine...

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, 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 is identified. FcγR-mediated cross-presentation is shown in type 2 and iDCs depend 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.