Plasmacytoid Dendritic Cells Surveil Megakaryocyte Sialic Acid to Regulate Thrombopoiesis

Sialic acid loss, such as exposure of the cryptic Thomsen-Friedenreich antigen (TF-antigen) occur during inflammation, in malignancies, and is associated with thrombocytopenia. Targeted deletion of O-glycan-specific sialyltransferase St3gal1 in megakaryocytes (MK) (St3gal1MK-/-) results in MK-restricted TF-antigen exposure and thrombocytopenia. We identified bone marrow (BM) plasmacytoid dendritic cells (pDCs) as regulators of thrombopoiesis in  St3gal1MK-/- mice. Lymphoid derived, BM resident pDCs engage directly through Siglec H with O-glycan sialic acid moieties to regulate type I interferon (IFN-I) secretion by pDCs and thrombopoiesis, as evidenced by normalized platelet count following deletion of Jak3 in St3gal1MK-/- mice and inhibition of interferon and Siglec H receptors. Single cell and bulk RNAseq of BM pDCs confirmed that TF-antigen exposure by MKs up-regulates IFN-I transcripts in pDCs and surprisingly reveals that Cd4-positive pDCs in the St3gal1MK-/- BM are primed to release IFN-I. Thus, MK sialic acid moieties regulate immune cells and thrombopoiesis in the BM.