Metabolic Control and Systems Immunology in Blood Cell Development

Coordination of metabolic programs with cell fate decisions is a fundamental determinant of hematopoietic cell development and function. Hematopoietic cells at different developmental and activation stages exhibit distinct metabolic signatures. Emerging evidence further highlights the interplay between cell signaling and metabolic programming in these processes. We found that myelopoiesis, including the differentiation of monocytes, macrophages and dendritic cells (DCs), required mechanistic target of rapamycin complex 1 (mTORC1) signaling and anabolic metabolism. Loss of mTORC1 impaired myelopoiesis under steady state and dampened innate immune responses against Listeria monocytogenes infection. Stimulation of hematopoietic progenitors with macrophage colony-stimulating factor (M-CSF) resulted in mTORC1-dependent anabolic metabolism, which in turn promoted expression of M-CSF receptor and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis. Mechanistically, mTORC1 engaged glucose metabolism and initiated a transcriptional program involving glycolysis and sterol biosynthesis after M-CSF stimulation. Integrative metabolomic and genomic profiling further identified one-carbon metabolism as a central node in mTORC1-dependent myelopoiesis. Moreover, we found that differentiation of DCs from bone marrow precursors was associated with dynamic regulation of mTORC1 signaling and cell metabolism. Either reduced or excessive mTORC1 activity was detrimental to DC development, associated with impaired regulation of cell metabolism. Interestingly, in contrast to the obligatory role of mTORC1 in monocyte and DC development, mTORC2 function was dispensable in these processes. Our results demonstrate that the interplay between mTORC1 signaling and bioenergetic and biosynthetic activities constitutes key metabolic checkpoints to orchestrate myelopoiesis. We are currently applying systems immunology approaches to explore metabolic signaling in myelopoiesis.