MHC II-expressing bone marrow megakaryocytes are noncanonical antigen-presenting cells and activate CD4+ T cells ex vivo

While professional antigen-presenting cells drive adaptive immunity, atypical cell types can fulfill this role in the bone marrow. Megakaryocytes (MKs) are canonically recognized for platelet production, but recent studies indicate functional heterogeneity and immune potential. We found that ∼20% of bone marrow MKs express major histocompatibility complex (MHC) II and co-stimulatory receptors CD80, CD86, CD40, and CD83. These MKs process and present antigen to activate T cells ex vivo in an MHC II-dependent manner. MK/T cell interactions induced TGF-β1 secretion and promoted induced regulatory T cell (Treg) differentiation. Toll-like receptor (TLR) stimulation of MKs elicited modest Th1-associated responses, including IFN-γ and TNF-α production, without robust Th17 differentiation. Immunopeptidomics confirmed peptide occupancy of MK MHC II in vivo . Using MK-targeted MHC II deletion, we observed altered TLR responses and reduced bone marrow TGF-β1. Together, these findings identify MHC II+ MKs as noncanonical antigen-presenting cells with potential roles in regulating CD4 + T cell responses within the bone marrow niche.