INFLUENCE OF TGF-BETA ON MURINE THYMOCYTE DEVELOPMENT IN FETAL THYMUSORGAN-CULTURE

TGF-beta is a multifunctional growth regulator that can either inhibit or stimulate the growth and differentiation of lymphocytes. For sever al cell types the effect of TGF-beta was found to correlate with the d ifferentiation stage of the cells. We have studied the influence of TG F-beta on the differentiation of murine thymocytes by evaluating the e ffect of TGF-beta on the generation of thymocyte subpopulations in fet al thymus organ culture. TGF-beta inhibited the growth and differentia tion of CD4(-)CD8(-) double-negative thymocytes. In the CD4(-)CD8(-) d ouble-negative cell population, most cells remained CD44(+)CD25(-), wi th CD44(+)CD25(+) and CD44(-)CD25(-) subpopulations dramatically decre ased in cell numbers. The accumulation of cells with a phenotype chara cteristic of cells in early stage of differentiation suggests a block at very early transition steps. These observations were confirmed in e xperiments with precursor cells from fetal liver transferred to 2-deox yguanosine-treated alymphoid thymic lobes, inasmuch as addition of TGF -beta caused a complete inhibition of T cell development. Differentiat ion into CD4(+)CD8(+) double-positive thymocytes and CD4(+) single-pos itive thymocytes was impaired because these cell numbers were greatly reduced. In contrast, the CD8(+) single-positive subpopulation retaine d normal cell numbers. This CD8(+) population had characteristics of a mature subset as the cells expressed CD8 beta and high levels of TCR- alpha beta and CD3. This TCR-alpha beta(+) cell population was not act ively dividing, suggesting that these cells arise de novo by different iation.