Functional Interaction between TGF-β and IL-12 in Human Primary Allogeneic Cytotoxicity and Proliferative Response

IL-12 is an important cytokine in the control of cell-mediated immunity. We have investigated the functional interaction of IL-12 with TGF-β₁, a cytokine involved in the regulation of growth and differentiation of immunocompetent cells, during human allogeneic response development. Using primary MLR, our data show that addition of exogenous TGF-β at the sensitizing phase of the primary MLR resulted in the inhibition of both allogeneic cytotoxic and proliferative responses. The inhibitory effect of TGF-β on allogeneic response involves an abrogation of IL-12/p70 production upon allostimulation. In contrast to its effect on IL-12 production, TGF-β did not alter the expression of IL-12R β₁-chain (IL-12Rβ) in T cells induced upon allogeneic activation. Addition of exogenous IL-12 or IFN-γ in the MLR cultures in the presence of TGF-β did not result in reversal of CTL generation and T cell proliferation. Interestingly, TGF-β was efficient in down-regulating IL-12 responsiveness of alloactivated T cells as well as TCR-αβ or TCR-γδ alloreactive T cell clones. These studies suggest that the inhibitory effect of TGF-β on the development of human allogeneic proliferation and cytotoxic responses involves an additional mechanism associated with an interference with IL-12 pathway.