Interleukin-12 can replace CD28-dependent T-cell costimulation during nonspecific cytotoxic T lymphocyte induction by anti-CD3 antibody

Cytotoxic T lymphocyte (CTL) development is regulated closely by as intrica te series of signals provided by the T-cell receptor/CD3 complex, cytokines , and costimulatory ligand/receptor systems. In this study, we have explore d the role of interleukin (IL)-12 and CD28 in mouse CTL development. Activa tion of T cells with anti-CD3 monoclonal antibody (mAb) in the presence of anti-CD86 mAb, which prevents CD28-CD86 interaction, Icd to decreased produ ction of type 1 (IL-2, interferon-gamma) slid type 2 (IL-4, IL-6, IL-10) cy tokines, us well as diminished expression of granzyme B (Gzm B) slid reduce d cytotoxic effector function. Cytolytic activity in T-cell cultures that w ere activated ill the presence of anti-CD86-blocking null alone or in combi nation with anti-CD80 mAb could be restored by the addition of exogenous IL -12 at initiation of culture. The ability of IL-12 to substitute for CD28-c ostimulatory signaling during CTL development was found to be dependent on the presence of IL-2 rather than interferon-gamma. IL-2 is required for IL- 12R beta2 expression by T cells activated ill the presence of anti-CD86 mAb , Moreover, IL-12R beta2 expression by T cells activated in the presence of anti-CD86 mAb is enhanced by IL-12. We, therefore, conclude that the abili ty of IL-12 to substitute for CD28-costimulatory signaling during CTL devel opment is a result of the interaction of IL-12 with IL-12R beta2 induced by low levels of IL-2 synthesized by T cells activated in a CD28-independent manner.