INTERLEUKIN (IL)-4, IN THE ABSENCE OF ANTIGEN STIMULATION, INDUCES AN ANERGY-LIKE STATE IN DIFFERENTIATED CD8(+) TC1 CELLS - LOSS OF IL-2 SYNTHESIS AND AUTONOMOUS PROLIFERATION BUT RETENTION OF CYTOTOXICITY AND SYNTHESIS OF OTHER CYTOKINES

Naive T cells in the periphery mainly secrete interleukin (IL) 2 upon activation. After stimulation in the presence of appropriate costimulators, both CD4(+) and CD8(+) T cells differentiate into effector cells secreting distinct T helper (Th) 1- and Th2-like cytokine patterns. Subsequent to differentiation both CD4(+) (Th1 and Th2) and CD8(+) (TC1 and TC2) cells are stable and cannot be induced to differentiate into the opposite pattern or revert to the naive cytokine secretion pattern. We now show that IL-4 caused committed TC1 bulk populations or clones to lose the ability to synthesize IL-2. The cells retained the ability to secrete interferon (IFN) gamma, granulocyte/macrophage colony-stimulating factor, and tumor necrosis factor, did not synthesize any Th2 cytokines, and did not alter cell surface marker expression. IL-4 rapidly inhibited IL-2-synthesizing ability in the absence or presence of antigen-presenting cells, thus demonstrating that IL-4 acted directly on TC1 cells. The defect in IL-2 synthesis could not be reversed by subsequent stimulation with potent antigen-presenting cells in the presence of IL-2 and anti-IL-4, or with anti-CD3 plus anti-CD28 antibodies. Both IL-2(+) and IL-2(-) TC1 cells were strongly cytotoxic toward allogeneic but not syngeneic targets. However, IL-2(-) TC1 cells were unable to proliferate unless exogenous IL-2 was provided. TC1 cells that lose IL-2 synthesis but retain IFN-gamma synthesis and cytotoxicity may be similar to the ''anerpic'' cells induced by stimulation of CD4(+) or CD8(+) cells in the absence of costimulators. These results suggest that during a mixed type 1/type 2 response in vivo, IL-4 may induce the IL-2(+) TC1 --> IL-2(-) TC1 conversion, and thus curtail the expansion of the TC1 response without impairing shea-term effector function.