A growing body of evidence shows that induction of long term transplant survival by costimulation blockade (CoB) regimens is impaired by inflammatory responses (e.g. engagement of toll like receptors). Type-1 interferons (TI-IFN) have been identified as mediators of this effect in multiple models, however, their target population and specific mechanism used to induce this effect remain unknown. Interleukin 10 (IL-10) is an immunomodulatory cytokine that despite its anticipated protective function in transplant tolerance, maintains a controversial role in the field. To better understand how an inflammatory environment, more specifically IFN-β, could interfere with the induction of transplant tolerance, we studied its impact on the immunomodulatory properties of IL-10.

Using a peri-transplant CoB regimen based on donor specific transfusion (DST) plus anti-CD154 (MR-1), our results showed that a concomitant, transient blockade of IL-10 signaling has a deleterious impact on the survival of murine full mismatch skin grafts (MST 105d vs 47d with anti-IL-10R). When replicating IFN-β exposure in vitro, 48h of co-culture caused in memory T cells (Tmem) and regulatory T cells (Tregs) a dramatic defect in the production of phospho-STAT3 in response to IL-10. This effect was very selective, as IL-6 signaling (post IFN-β exposure) induced normal levels of phospho-STAT3. Encouragingly, this inhibition of IL-10 signaling was slowly reversible with the removal of TI-IFN. Our data indicated that this IL-10-specific unresponsiveness was not associated with any reduction of IL-10R expression or an increase in SOCS1 and 3, nor with a reduced STAT3 cytoplasmic availability. Instead, they suggested a novel role for the transcription factor STAT1 in dampening IL-10 signaling. Using STAT1-KO T cells we show that its absence prevented IL-10 inhibition induced by IFN-β in Treg and Tmem, supporting our new model.

Overall, these results highlight the importance of IL-10 signaling in the therapeutic effect of CoB regimens in transplantation. More importantly, they reveal a new molecular mechanism whereby IFN-β interferes with IL-10 signaling, its suppressive function in T cells, and ultimately with regulation of alloreactivity. Identifying a strategy to target this mechanism will be a powerful tool to improve the efficacy of immunomodulatory strategies for transplant tolerance induction.

CITATION INFORMATION: Iglesias M., Arun A., Chicco M., Lam B., Ivanova V., Lee W., Brandacher G., Raimondi G. Type-1 Interferon Impairs the Immunoregulatory Activity of IL-10: Understanding the Mechanisms of Abrogation of Transplant Tolerance Am J Transplant. 2017;17 (suppl 3).

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