Spatially restricted JAG1-Notch signaling in human thymus provides suitable DC developmental niches

Abstract

A key unsolved question regarding the developmental origin of conventional and plasmacytoid dendritic cells (cdcs and pdcs, respectively) resident in the steady-state thymus is whether early thymic progenitors (EtPs) could escape t cell fate constraints imposed normally by a notch-inductive microenvironment and undergo dc development. By modeling dc generation in bulk and clonal cultures, we show here that Jagged1 (JAG1)-mediated notch signaling allows human EtPs to undertake a myeloid transcriptional program, resulting in GAtA2-dependent generation of cd34+ cd123+ progenitors with restricted pdc, cdc, and monocyte potential, whereas delta-like1 signaling down-regulates GAtA2 and impairs myeloid development. Progressive commitment to the dc lineage also occurs intrathymically, as myeloid-primed cd123+ monocyte/dc and common dc progenitors, equivalent to those previously identified in the bone marrow, are resident in the normal human thymus. the identification of a discrete JAG1+ thymic medullary niche enriched for dc-lineage cells expressing notch receptors further validates the human thymus as a dc-poietic organ, which provides selective microenvironments permissive for dc development.