C-Myc regulation by Notch Signaling Modulates T Cell Differentiation

Abstract Notch signaling is essential for T lineage commitment and further required during early phases of thymocyte differentiation. Active Notch signaling during early stages of T cell development inhibits other lineage potentials, such as B cell and myeloid cell (e.g., dendritic cell) potentials. However, the intracellular signaling pathways by which Notch signaling regulates T cell differentiation remain unknown. Here we show that the transcriptional factor c-Myc is controlled by Notch signaling which regulates T cell differentiation. In a well-established in vitro differentiation of T lymphocytes from stem cells, Notch signaling directly controls c-Myc expression. Overexpression of active c-Myc promotes while dominant-negative (dn) c-Myc inhibits early cell differentiation. Moreover, c-Myc expression mediated by Notch signaling modulates survivin, an inhibitor of apoptosis (IAP) protein, which is crucial for T cell development. Overexpression of active c-Myc increases while dn c-Myc reduces survivin expression, which corresponds to T cell differentiation within the in vitro differentiation system. These results identify c-Myc, together with survivin, as regulators of the differentiation of T cells from Notch signaling.