The clonal and molecular aetiology of emergency dendritic cell development
Lin, D. S.; Tian, L.; Tomei, S.; Amann-Zalcenstein, D.; Baldwin, T. M.; Weber, T. S.; Schreuder, J.; Stonehouse, O.; Rautela, J.; Huntington, N. D.; Ng, A. P.; Nutt, S. L.; Taoudi, S.; Ritchie, M. E.; Hodgkin, P. D.; Naik, S. H.
Show abstract
Extrinsic regulation of single haematopoietic stem and progenitor cell (HSPC) fate is crucial for immune cell development. Here, we examine the aetiology of Flt3 ligand (Flt3L)-mediated emergency development of type 1 conventional dendritic cells (cDC1s), which results in enhanced immunity against infections and cancer. Using cellular barcoding, we demonstrate a predominant role of enhanced clonal expansion and moderate contribution via recruitment of additional cDC1-generating HSPCs. The selective cDC1 expansion occurs primarily via multi-/oligo-potent clones, without compromising output to other lineages. To understand the molecular hallmarks early during a Flt3L response, we develop Divi-Seq to simultaneously profile cell division history, surface phenotype and transcriptional state of single HSPCs. We discover that Flt3L-responsive HSPCs maintain a proliferative early progenitor-like state, which leads to selective emergence of CD11c+cKit+ transitional precursors with high cellular output to cDC1s. These findings inform the mechanistic action of Flt3L in natural immunity and immunotherapy at a clonal level.
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