The role of TGF-g 1 in the regulation of T cell responses has been perplexing, possibly because it is dependent on the type of T cell being regulated and its cytokine microenvironment. In the present study, we demonstrate that TGF-g 1 has a profound inhibitory effect on naive CD4 + T cell undergoing differentiation under defined neutral, Th1 and Th2 priming conditions. In addition, we show that if CD4 + T cells are primed in the presence of TGF-g 1, they exhibit reduced secondary anti-CD3/anti-CD28-induced and antigen-specific immune responses (even when TGF-g is absent during the secondary response), which is not due to reduced expression of co-stimulatory molecules or to inadequate IL-2 production. Finally, with respect to the effect of TGF-g on fully differentiated antigen-specific memory CD4 + T cells, we demonstrate that while antigen-specific activation and cytokine secretion by memory Th1 T cells is inhibited by TGF-g 1, such inhibition is associated with partial downregulation of IL-12 receptor g 2 chain expression. In contrast, memory Th2 T cells are not subject to TGF-g 1-mediated suppression. In summary, these studies reveal that TGF-g 1 is a powerful negative regulator of the primary immune response of CD4 + T cells, but only Th1 T cells are subject to such regulation after the memory stage of T cell differentiation has been reached. Thus, these studies define the potential regulatory role of TGF-g 1 in Th1 and Th2 T cell-mediated autoimmunity.