INDUCTION OF INTERLEUKIN-12 RESPONSIVENESS IS IMPAIRED IN ANERGIC T-LYMPHOCYTES

The cytokine, interleukin 12 (IL-12), stimulates both natural killer c ells and T cells to proliferate and to secrete interferon gamma (IFN-g amma). The T cell proliferative response to IL-12 must be induced and is evident after T cell receptor-mediated stimulation. As reported her e, tolerant CD4(+) T cells and clones, that are anergic for IL-2 produ ction, are also anergic for induction of the proliferative response to IL-12. Murine T helper 1 clones tolerized in vitro, as well as anergi c CD4(+) T cells isolated from mice tolerized to the Mls-1(a) antigen (Ag) in vivo, demonstrated defective induction of proliferation to IL- 12 upon restimulation with Ag. IL-12-enhanced production of IFN-gamma was observed in both control and anergic cells after Ag/antigen-presen ting cell (APC) activation, although total IFN-gamma secretion by aner gic cells was less than that produced by control cells, even in the pr esence of IL-12. These data indicate that T cell clonal anergy results in profound inhibition of proliferative responses, since the autocrin e growth factor, IL-2, is not produced, and the APC-derived cytokine, IL-12, is not an effective stimulus for anergic T cell proliferation.