Interleukin-12 (IL-12)-driven alloimmune responses in vitro and in vivo - Requirement for beta 1 subunit of the IL-12 receptor

Background. Interleukin-12 (IL-12) mediates its biologic activities via bin ding high-affinity receptors on T and natural killer cells. Although emphas is has been placed on the requirement for IL-12R beta 2 in IL-12 bioactivit y, the role of IL-12R beta 1 is less well defined. The current study evalua ted the effects of exogenous IL-12 on alloantigen-specific immune responses and determined the requirement for IL-12R beta 1 in IL-12-mediated alloimm unity, Methods, The mouse heterotopic cardiac transplant model was employed to eva luate the effects of IL-12 on alloantigen-specific immune responses in vivo . In addition, IFN-gamma production in mixed lymphocyte cultures (MLC) supp lemented with IL-12 was measured to assess the effects of IL-12 on Th1 func tion in vitro. Mice deficient in IL-12R beta 1 (IL-12R beta 1(-/-)) were us ed to determine the requirement for this receptor component in IL-12-driven alloimmune responses. Results, Addition of IL-12 to MLC consisting of wildtype splenocytes enhanc ed alloantigen-specific proliferative responses and Th1 development. In con trast, IL-12 did not alter these in vitro immune parameters in IL-12R beta 1(-/-) MLC. Treatment of wild-type cardiac allograft recipients with IL-12 resulted in high concentrations of serum interferon-gamma (IFN-gamma) and a 10-fold increase in IFN-gamma production by recipient splenocytes after re stimulation in vitro. However, this fulminate Th1 response did not accelera te allograft rejection. Importantly, IL-12 had no effect on serum IFN-gamma or in vivo priming of Th1 in IL-12R beta 1(-/-) recipients. Finally, admin istration of IL-12 to WT allograft recipients resulted in a bimodal alloant ibody response: antibody production was suppressed at high doses of IL-12, and enhanced at lower doses. Conclusions, IL.12 markedly enhances alloantigen-specific immune function; however, these exaggerated Th1-driven responses do not culminate in acceler ated allograft, rejection. Further, these data indicate that IL-12R beta 1 is essential for the enhancement of both in vitro and in vivo alloimmune re sponses by exogenous IL-12.