Inhibition of lymphocyte activation and function by the prenylation inhibitor L-778,123

Abstract

Prenylated Ras GTPases transduce signals from the T cell receptor, CD28 costimulatory receptor and IL-2 receptor. Since signals from these receptors mediate T cell activation, proliferation and survival, we hypothesized that the prenylation inhibitor L-778,123 would impart immunomodulation. The effect of L-778,123 on T cell activation (CD71 or CD25 surface expression) was determined by flow cytometry. Peripheral blood mononuclear cell (PBMC) proliferation in the presence of L-778,123 and/or cyclosporine (CsA) was determined by [3H]thymidine incorporation. The ability of L-778,123 to inhibit IL-2 receptor signaling was investigated by measuring IL-2 induced proliferation in CTLL-2 cells and IL-2 prevention of apoptosis in activated human PBMC. L-778,123 inhibited lectin induced expression of CD71 and CD25 with IC50's of 6.48 +/- 1.31 microM and 84.1 +/- 50.0 microM, respectively. PBMC proliferation was inhibited by L-778,123 with an IC50 of 0.92 +/- 0.23 microM, and addition of CsA did not increase the potency. L-778,123 did not inhibit IL-2 and IFN-gamma production by T cells. L-778,123 abrogated IL-2 induced proliferation of CTLL-2 cells with an IC50 of 0.81 +/- 0.44 microM. However, L-778,123 minimally reversed the prosurvival effect of IL-2 in activated lymphocytes. IL-2 ligand and receptor production during T cell activation are relatively unaffected by L-778,123. However, the activation and proliferative effects of IL-2 on T cells are potently blocked by L-778,123. These results reveal a selective blockade of the IL-2 cytokine axis distal to the IL-2 receptor by the L-778,123 and warrant evaluation of prenylation inhibitors in treating transplant rejection and autoimmune diseases.