Abstract
Understanding the pathways and regulation of human haematopoiesis, in particular, lymphopoiesis, is vital to manipulation of these processes for therapeutic purposes. However, although haematopoiesis has been extensively characterised in mice, translation of these findings to human biology remains rudimentary. Here, we describe the isolation of three progenitor subsets from human foetal bone marrow that represent differential stages of commitment to the natural killer (NK) cell lineage based on IL-15 responsiveness. We identify CD7 as a marker of IL-15 responsive progenitors in human bone marrow and find that this expression is maintained throughout commitment and maturation. Within the CD7+ fraction, we focussed on the lineage potential of three subsets based on CD127 and CD117 expression and observed restricted lymphoid and biased NK cell potential amongst subsets. We further demonstrate the presence of subsets similar in both phenotype and function in umbilical cord blood and the bone marrow of humanised mice, validating these as appropriate sources of progenitors for the investigation of human haematopoiesis. Overall, we describe several stages in the process of lymphopoiesis that will form the basis of investigating the regulators of this process in humans.
Highlights
Despite extensive progress in our understanding of the pathways and regulation of murine haematopoiesis, our knowledge of these processes in humans remains undeveloped
Renoux et al identified a downstream natural killer (NK) cell-restricted progenitor within the Lin−CD34+CD7+CD10+ fraction as a human equivalent of the murine NK cell progenitor (NKP) [8]. Both lymphoid primed multipotent progenitors (LMPP) and “common lymphoid progenitors (CLP)-like” cells gave rise to these progenitors in vitro, suggesting the NKP described is a stage in the physiological process of NK cell development. To track these intermediate stages in which loss of myeloid, T and B cell potential and commitment to the NK cell lineage occurs, we have focused on the only factor known to be essential for human and murine NK cell development, IL-15 [9,10,11,12], sensitivity to which marks murine NK cell lineage commitment [13,14,15]
We previously reported an expansion of mature CD7+CD56+ NK cells in the spleen and noted a robust expansion of lineage− cells in the bone marrow (BM) of human immune system mice following treatment with IL-15 receptor agonists [11]
Summary
Despite extensive progress in our understanding of the pathways and regulation of murine haematopoiesis, our knowledge of these processes in humans remains undeveloped. Renoux et al identified a downstream NK cell-restricted progenitor within the Lin−CD34+CD7+CD10+ fraction as a human equivalent of the murine NK cell progenitor (NKP) [8] Both lymphoid primed multipotent progenitors (LMPP) and “CLP-like” cells gave rise to these progenitors in vitro, suggesting the NKP described is a stage in the physiological process of NK cell development. To track these intermediate stages in which loss of myeloid, T and B cell potential and commitment to the NK cell lineage occurs, we have focused on the only factor known to be essential for human and murine NK cell development, IL-15 [9,10,11,12], sensitivity to which marks murine NK cell lineage commitment [13,14,15]. We expect these findings will provide a framework for future studies investigating the regulation of human lymphopoiesis
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