Discovery of highly immunogenic spleen-resident FCGR3^(+)CD103^(+)cDC1s differentiated by IL-33-primed ST2^(+)basophils

摘要

Recombinant interleukin-33(IL-33)inhibits tumor growth,but the detailed immunological mechanism is still unknown.IL-33-mediated tumor suppression did not occur in Batf3^(−/−)mice,indicating that conventional type 1 dendritic cells(cDC1s)play a key role in IL-33-mediated antitumor immunity.A population of CD103^(+)cDC1s,which were barely detectable in the spleens of normal mice,increased significantly in the spleens of IL-33-treated mice.The newly emerged splenic CD103^(+)cDC1s were distinct from conventional splenic cDC1s based on their spleen residency,robust effector T-cell priming ability,and surface expression of FCGR3.DCs and DC precursors did not express Suppressor of Tumorigenicity 2(ST2).However,recombinant IL-33 induced spleen-resident FCGR3^(+)CD103^(+)cDC1s,which were found to be differentiated from DC precursors by bystander ST2+immune cells.Through immune cell fractionation and depletion assays,we found that IL-33-primed ST2^(+)basophils play a crucial role in the development of FCGR3^(+)CD103^(+)cDC1s by secreting IL-33-driven extrinsic factors.Recombinant GM-CSF also induced the population of CD103^(+)cDC1s,but the population neither expressed FCGR3 nor induced any discernable antitumor immunity.The population of FCGR3^(+)CD103^(+)cDC1s was also generated in vitro culture of Flt3L-mediated bone marrow-derived DCs(FL-BMDCs)when IL-33 was added in a pre-DC stage of culture.FL-BMDCs generated in the presence of IL-33(FL-33-DCs)offered more potent tumor immunotherapy than control Flt3L-BMDCs(FL-DCs).Human monocyte-derived DCs were also more immunogenic when exposed to IL-33-induced factors.Our findings suggest that recombinant IL-33 or an IL-33-mediated DC vaccine could be an attractive protocol for better tumor immunotherapy.