TGF-β1 is an important pleiotropic cytokine that has been described to have both stimulatory and inhibitory effects on cell growth and differentiation. For several cell types, the effect of TGF-β1 was found to correlate with the differentiation stage of the cells and the presence of other cytokines. In this report, we address the influence of TGF-β1 on CD4+ T cell activation by evaluating the effect of TGF-β1 on the proliferative and cytokine responses of purified resting and activated human or mouse CD4+ T cells. TGF-β1 inhibits proliferation and cytokine secretion on resting CD4+ T cells but has no inhibitory effect on activated T cells. Moreover, TGF-β1 unresponsiveness of activated T cells was correlated with a down-regulation in the expression of the TGF-β receptor type II. Interestingly, IL-10 addition enhances TGF-β receptor type II expression and restores TGF-β responsiveness on activated T cells. These results indicated that TGF-β responsiveness is sequentially regulated on T cells by the modulation of the of TGF-β receptor type II chain expression. Moreover, we have identified a novel regulatory role of IL-10 on TGF-β-dependent T cell growth that can explain the control of T cell activation on chronic vs acute inflammatory sites.