Notch ligands potentiate IL-7-driven proliferation and survival of human thymocyte precursors

Notch and IL-7 are both well-characterized factors involved in T-cell development. In contrast to the mouse model, their precise requirements in the differentiation and/or proliferation of various stages of human thymic development have not been fully explored. Here, we demonstrate that IL-7 alone is sufficient to induce the differentiation of ex vivo purified CD34⁺ triple negative (TN) surface (s) CD3^- CD4^-CD8^- (CD3^-CD4^-CD8^-), CD4 immature single positive (ISP) (sCD3^-CD4⁺CD8^-) and double positive (DP) (sCD3^-CD4⁺ CD8⁺) human thymic precursors to mature DP expressing sCD3 (sCD3⁺CD4⁺CD8⁺). We show that activation of Notch signaling by its ligands Delta-1 or Delta-4 potentiates IL-7-driven proliferation and survival of CD34⁺ TN and to a lesser extent of CD4⁺ ISP precursors. This effect of Notch is related to a sustained induction of IL-7 receptor α chain expression on thymocytes through a decreased methylation of its gene promoter. Thus, we show here that proliferation and differentiation of T-cell precursors are differentially modulated by IL-7 depending on the presence or absence of external signals. These results may have important implications for the clinical use of this cytokine as a strategy aimed at improving immune restoration.