Immune subtypes of megakaryocytes orchestrate inflammatory and regulatory responses to pulmonary infection via Treg crosstalk.

Recent studies have revealed that, beyond their classical role in platelet production, megakaryocytes (MKs) express immune-related genes and exert important immunoregulatory functions. However, it remains unclear whether these functions arise from a single versatile population or from distinct specialized subtypes, and how such subtypes influence infection and inflammation. Here, we identified three specialized immune MK subtypes (imm-MKs)-macrophage-like MKs (Mac-MKs), neutrophil-like MKs (Neu-MKs), and antigen-presenting MKs (APC-MKs)-each defined by distinct transcriptional programs and regulatory networks, with comparable heterogeneity observed in human MKs. Developmental analyses showed that MK immune-related programs increased with maturation and that immune MK subtypes exhibited distinct tissue- and stage-dependent patterns. Functionally, MK subtypes exhibited phase-specific responses during bacterial pneumonia: early infection preferentially induced Mac-MKs and Neu-MKs, which contributed to pulmonary inflammation, whereas during the post-peak acute-to-early-recovery stage, APC-MKs supported a Treg-associated regulatory program that contributed to pulmonary inflammatory control. This MK-Treg axis uncovers a previously unrecognized mechanism of hematopoietic-immune crosstalk. Collectively, our study delineates organ- and stage-specific immune specialization of MKs and identifies immune MK subtypes as dynamic contributors to phase-specific inflammatory and Treg-linked regulatory programs during development and infection.