Notch1 and IL-7 receptor interplay maintains proliferation of human thymic progenitors while suppressing non-T cell fates.

摘要: Notch signaling is critical for T cell development of multipotent hemopoietic progenitors. Yet, how regulates fate specification during early thymopoiesis remains unclear. In this study, we have identified an subset CD34 high c- kit + flt3 IL-7Rα cells in the human postnatal thymus, which includes primitive progenitors with combined lymphomyeloid potential. To assess impact development, expressed constitutively active Notch1 such thymic precursors (TLMPs), or triggered their endogenous pathway OP9-Delta-like1 stroma coculture. Our results show that proliferation vs differentiation a decision influenced by at TLMP stage. We found plays prominent role inhibiting non-T (i.e., macrophages, dendritic cells, and NK cells) TLMPs, while sustaining undifferentiated thymocytes potential response to unique IL-7 signals. However, activation not sufficient inducing T-lineage progression proliferating Rather, stroma-derived signals are concurrently required. Moreover, ectopic IL-7R expression cannot replace maintenance expansion thymocytes, sustain induce up-regulation line. Thus, pathways cooperate synchronize suppression lineage choices intrathymic progenitors, will be allowed progress along only upon interaction inductive stromal microenvironment. These data provide insight into mechanism Notch-regulated amplification pool