IL-6-C/EBPβ signaling drives monocytic differentiation of murine cultured lymphoid progenitors with immunoregulatory properties

While lymphoid progenitors have demonstrated unexpected plasticity in vivo, their differentiation into myeloid cells under in vitro conditions has been largely dismissed as an artifact or biologically irrelevant. Consequently, the functional properties of these cells remain poorly characterized. In this study, we show that cultured common lymphoid progenitors (cCLPs) differentiate into CD11b⁺CD115⁺ monocytic cells (cCLP-Ms) via IL-6-C/EBPβ signaling. Molecular and phenotypic analyses revealed that cCLP-Ms acquire essential features of myeloid cells, including innate immune sensor expression and phagocytic capacity, while retaining unique characteristics distinct from bone marrow-derived macrophages (BMDMs), such as reduced MHC class II expression and TNF-α production. Functionally, cCLP-Ms exhibit immunoregulatory properties, effectively suppressing IgE-mediated cutaneous allergic inflammation upon adoptive transfer. These findings highlight the plasticity of lymphoid progenitors and establish a robust platform for investigating the mechanisms underlying myeloid differentiation. This system deepens our understanding of hematopoietic cell lineage flexibility and offers a foundation for exploring therapeutic applications in immune regulation and inflammation.