Type-1 Interferons impair the immunoregulatory activity of IL-10: understanding novel mechanisms of abrogation of transplant tolerance

Abstract

Abstract Induction of long term transplant survival by “costimulation blockade” (CoB) regimens is impaired by inflammatory responses. Type-1 interferons (TI-IFNs) are recognized mediators of this effect in multiple models, but their target population and specific mechanism used remain undefined. To better understand how TI-IFN could interfere with transplant tolerance, we studied their impact on the immunomodulatory properties of IL-10. Using a murine full-mismatch skin transplant model we showed that IL-10 has a fundamental role in the protective effect of CoB. Bone marrow chimeras suggested this effect is partially dependent on IL-10 signaling in T cells. We then studied the impact of T cell exposure to TI-IFN on IL-10 signaling. Following in vitro exposure, T cells produced significantly less phospho-STAT3 in response to IL-10. This effect was very selective - IL-6 signaling remained unaltered - and resulted in the inhibition of specific IL-10 induced genes. Encouragingly, this effect was slowly reversible with removal of TI-IFN, suggesting a “druggable” pathway. This unresponsiveness was not associated with reduced IL-10-receptor expression or increased SOCS1_3 levels. Instead, microarray analysis of exposed cells suggested a novel role for STAT1 in dampening IL-10 signaling. Preliminary experiments with STAT1-KO cells supported this hypothesis. Overall, these results highlight the importance of IL-10 in the efficacy of CoB regimens and reveal a new molecular mechanism whereby TI-IFNs can interfere with IL-10 signaling, and ultimately with the regulation of alloreactivity. A strategy to selectively target this mechanism could significantly enhance the clinical efficacy of CoB-based immunomodulatory strategies.