DIFFERENTIAL EFFECT OF TRANSFORMING GROWTH-FACTOR-BETA-1 ON THE ACTIVATION OF HUMAN NAIVE AND MEMORY CD4(+) T-LYMPHOCYTES

Transforming growth factor-beta 1 (TGF-beta 1) can have stimulatory or inhibitory effects on cell growth. For several cell types, the effect of TGF-beta 1 was found to correlate with the differentiation stage of the cells and the presence of other cytokines. We have studied here the influence of TGF-beta 1 on CD4(+) T cell activation in relation to the differentiation stage of the cells by evaluating the effect of TGF-beta 1 on the proliferative responses of purified CD4(+)CD45RA(+) (unprimed) and CD4(+)CD45RO(+) (primed) lymphocytes. Under certain conditions, TGF-beta 1 exerted a co-stimulatory effect on peripheral blood CD4(+)CD45RA(+) T cells whereas the outgrowth of CD4(+)CD45RO(+) T cells was suppressed in any activation system tested. The enhancement of proliferative responses by TGF-beta 1 in TCR/CD3 or CD2 stimulated cultures of CD45RA(+) cells involved up-regulation of CD25 expression and was dependent on the presence of exogenous IL-2 or CD28 mAbs; IL-7 driven proliferative responses were suppressed by TGF-beta 1. These observations were confirmed in experiments with purified cord blood (CB) CD4(+) T cells inasmuch as addition of TGF-beta 1 caused a 2- to 7-fold increase in IL-2 driven proliferative responses of these cells. Finally we show that, in contrast to the effect of TGF-beta 1 during primary stimulation of CB CD4(+) T cells, TGF-beta 1 suppressed T cell proliferation for similar to 40% in secondary cultures of these cells. Our findings indicate that TGF-beta 1 is a bifunctional regulator of CD4(+) T cell growth in vitro, with co-stimulatory capacities during CD45RA(+) T cell mediated primary responses and growth suppressive effects during secondary responses of CD45RO(+) T cells.