Notch1 regulates maturation of CD4(+) and CD8(+) thymocytes by modulating TCR signal strength

Notch signaling regulates cell fate decisions in multiple lineages. We demo nstrate in this report that retroviral expression of activated Notch1 in mo use thymocytes abrogates differentiation of immature CD4(+)CD8(+) thymocyte s into both CD4 and CD8 mature single-positive T cells. The ability of Notc h1 to inhibit T cell development was observed in vitro and in vivo with bot h normal and TCR transgenic thymocytes. Notch1-mediated developmental arres t was dose dependent and was associated with impaired thymocyte responses t o TCR stimulation. Notch1 also inhibited TCR-mediated signaling in Jurkat T cells. These data indicate that constitutively active Notch1 abrogates CD4 (+) and CD8(+) maturation by interfering with TCR signal strength and provi de an explanation for the physiological regulation of Notch expression duri ng thymocyte development.