The role of IL-6 in hyperlipidemia-induced accelerated rejection

Abstract

Hyperlipidemia induces accelerated rejection of cardiac allografts and resistance to tolerance induction using costimulatory molecule blockade in mice due in part to anti-donor Th17 responses and reduced regulatory T cell function. Accelerated rejection in hyperlipidemic mice is also associated with increased serum levels of IL-6. Here, we examined the role of IL-6 in hyperlipidemia-induced accelerated rejection and resistance to tolerance. Genetic ablation of IL-6 prevented hyperlipidemia-induced accelerated cardiac allograft rejection. Using Th17-lineage fate tracking mice, we observed that IL-6 is required to promote the development of anti-donor Th17lineage cells independently of antigen challenge. In contrast, the frequency of alloreactive T cells producing IL-2 or IFN-γ remained increased in hyperlipidemic IL-6-deficient mice. Ablation of IL-6 overcame hyperlipidemia-induced changes in Tregs, but was not sufficient to overcome resistance to costimulatory molecule blockade induced tolerance. We suggest that accelerated rejection in hyperlipidemic mice results from IL-6 driven anti-donor Th17 responses. While alterations in Tregs were overcome by ablation of IL-6, the reversal of hyperlipidemia-induced changes in Tregs was not sufficient to overcome increased Th1-type anti-donor T cell responses, suggesting that hyperlipidemia induced IL-6-independent effects on recipient immunity prevent tolerance induction.