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-{beta}1 secretion and promoted induced Treg differentiation. Prior stimulation of MKs with LPS or Poly I:C was associated with modest Th1-associated CD4+ T cell responses, including IFN-{gamma} and TNF- production, without robust Th17 differentiation. Immunopeptidomics of the murine MK MHC II receptor confirmed occupancy by exogenous peptides, suggesting in vivo functionality. Using a murine model with MK-targeted deletion of MHC II (Pf4-MHC{Delta}/{Delta}), we observed altered TLR signaling and reduced bone marrow TGF-{beta}1. Together, these findings identify MHC II+ MKs as noncanonical antigen-presenting cells with the potential to modulate CD4 T cell responses as part of the immune regulation of the bone marrow niche.