CRITICAL INVOLVEMENT OF TCF-1 IN EXPANSION OF THYMOCYTES

T cell maturation in TCf-1(-/-) mice deteriorates progressively and ha lts completely around 6 mo of age. During fetal development thymocyte subpopulations seem normal, although total een numbers are lower. By 4 to 6 wk of age, obvious blockades in the differentiation of CD4(-)8(- ) thymocytes are observed at two distinct stages (CD44(+)25(+) and CD4 4(-)25(-)), both of which are normally characterized by extensive prol iferation, This lack of thymocyte expansion and/or differentiation was also observed when Tcf-1(-/-) progenitor cells from the aorta-gomad-m esonephros region (embryonic day 11.5), fetal Liver (embryonic day 12. 5/14.5), and fetal bone marrow (embryonic day 18.5) mere allowed to di fferentiate in normal thymic lobes (fetal thymic organ cultures) or we re injected into intrathymically into normal recipients. Despite these apparent defects in thymocyte differentiation and expansion, adult Tc f-1(-/-) mice are immunocompetent, as they generate virus neutralizing Abs at normal titers, Furthermore, their peripheral T cells have an a ctivated phenotype (increased CD44 and decreased CD62L expression) and proliferate normally in response to Bg or mitogen, suggesting that th ese cells snap have arisen from the early wave of development during e mbryogenesis and are either long lived or have subsequently been maint ained by peripheral expansion. As Tcf-1 is a critical component in the Wnt/beta-catenin signaling pathway, these data suggest that Wnt-like factors play a role in the expansion of double-negative thymocytes.