Differential effects of IL-12 receptor blockade with IL-12 p40 homodimer on the induction of CD4+ and CD8+ IFN-gamma-producing cells.

The role of IL-12 role in regulating Th1/Th2 balance is attributed in part to the ability of this cytokine to induce IFNgamma production by NK and Th1 cells, which in turn promotes Th1 and inhibits Th2 development. In the present study, the requirement for IL-12 in the development of alloantigen-reactive Th1 was assessed by adding neutralizing anti-IL-12 Abs or the IL-12 receptor antagonist p40 homodimer to primary MLC. The resulting cell populations were assessed for Th1 development by measuring IFN-gamma production upon restimulation with alloantigens. While the addition of anti-IL-12 Abs to primary MLC did not influence subsequent cytokine production, addition of p40 homodimer markedly enhanced, rather than decreased, Th1 development. To determine which T cell population produced enhanced levels of IFN-gamma in response to p40 homodimer, CD4+ or CD8+ T cells were depleted from the MLC. While p40 homodimer was inhibitory to selected CD4+ Th1 development, it enhanced IFN-gamma production by CD8+ T cells. To test the in vivo relevance of these findings, mouse heterotopic cardiac allograft recipients were treated with either p40 homodimer, anti-CD8 mAb, or with both p40 homodimer and anti-CD8 mAb. Treatment of allograft recipients with p40 homodimer had no effect on the in vivo sensitization of IFN-gamma-producing cells and resulted in accelerated allograft rejection relative to unmodified recipients. However, p40 homodimer markedly prolonged allograft survival in mice depleted of CD8+ T cells. Hence, p40 homodimer stimulates CD8+ Th1 development in vitro but inhibits CD4+ T cell function both in vitro and in vivo.