Nutritional Retinoic Acid as an early cDC2A fate instructive signal in the bone marrow

ongoing

cDcIVA aims to reveal a gut-bone marrow axis mediated by retinoic acid (RA) as a fate-instructive factor for the development of conventional dendritic cell (cDC) precursors in the bone marrow. Communication between the intestine and other organs, such as the bone marrow is mediated by several nutrients, including Vitamin A. This proposal focuses on examining how the Vitamin A derivative, RA, reaches the bone marrow and boosts the output of a specific RA-responsive cDC subset with implications on predisposing certain effector functions of the adaptive immune system. By integrating in vitro differentiation assays, spatial transcriptomics, and in vivo RA manipulations (genetically and pharmacologically), this proposal aims to: 1) establish the role of Vitamin A, as a mediator of the gut-bone marrow axis, in regulating cDC development, 2) demonstrate that retinoic acid is the sole Vitamin A metabolite that can have cell intrinsic effects on cDC progenitors and 3) reveal the cells that metabolise and supply RA to cDC progenitors and form part of an instructive bone marrow niche. cDcIVA will advance our understanding of how the interplay between nutrition and immunity can regulate the development of the cells that govern the effector functions of the adaptive immune system, offering valuable insights for future research in vaccination and cancer immunotherapy.