Interleukin-12 (IL-12)-driven alloimmune responses in vitro and in vivo -: Requirement for β1 subunit of the IL-12 receptor

Background. Interleukin-12 (IL-12) mediates its biologic activities via binding high-affinity receptors on T and natural killer cells. Although emphasis has been placed on the requirement for IL-12R beta 2 in IL-12 bioactivity, the role of IL-12R beta 1 is less well defined. The current study evaluated the effects of exogenous IL-12 on alloantigen-specific immune responses and determined the requirement for IL-12R beta 1 in IL-12-mediated alloimmunity, Methods, The mouse heterotopic cardiac transplant model was employed to evaluate the effects of IL-12 on alloantigen-specific immune responses in vivo. In addition, IFN-gamma production in mixed lymphocyte cultures (MLC) supplemented with IL-12 was measured to assess the effects of IL-12 on Th1 function in vitro. Mice deficient in IL-12R beta 1 (IL-12R beta 1(-/-)) were used 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 enhanced alloantigen-specific proliferative responses and Th1 development. In contrast, 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 restimulation in vitro. However, this fulminate Th1 response did not accelerate 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, administration of IL-12 to WT allograft recipients resulted in a bimodal alloantibody 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 accelerated allograft, rejection. Further, these data indicate that IL-12R beta 1 is essential for the enhancement of both in vitro and in vivo alloimmune responses by exogenous IL-12.