Introduction: Balancing immunity and immunopathology at the sites of inflammation requires coordination of effector and regulatory immune mechanisms. Local immune responses to the infection, mechanical insult or an allograft result in the release of inflammatory mediators such as TLR ligands or proinflammatory cytokines. The ability of regulatory T cells (Treg) cells to respond to and suppress in the presence of inflammatory mediators is still not fully understood.  From the perspective of clinical translation of Treg cell therapy for the organ transplantation, the investigation of the ability of Treg cells to mediate suppression in inflammatory conditions is extremely important.  In this study, we investigated the impact of physiological amounts of IL-1β on Treg-mediated suppression and role of a decoy IL-1 receptor (IL-1RII) in Tregs ability to regulate the immune response.
Material and Methods: Sorted CD127loCD25+CD4+ human Tregs and CD127+CD25-CD4+ T effector cells (Teffs) have been expanded in vitro in the presence of anti-CD3/CD28 beads and recombinant IL-2 and the expression of IL-1 receptors have been evaluated using qPCR.  Using co-culture experiments we tested the effects of IL-1β on the alloresponse and Tregs suppression.  Next, utilising lentiviral IL-1RII silencing, neutralising antibodies and a combination of proliferation assays, intracellular signalling and cytokine production measurements we assessed the role of IL-1RII in human Tregs.
Results: Here, we demonstrated that physiological amounts of exogenousIL-1β significantly enhanced the proliferation and cytokine production by human T cells upon allostimulation.  Interestingly, at high dose Tregs could neutralise the effect of IL-1β on both proliferation and cytokine secretion.  When assessed for expression of IL-1 receptors, Treg cells responded to activation with increased expression of a decoy IL-1 receptor, IL-1RII, and by releasing soluble IL-1RII into the local microenvironment, whereas the expression of signal transducing receptor, IL-1RI, was similar in Treg and T effector cells.  Next, using lentiviral silencing, we demonstrated that IL-1RII expression by human Tregs is necessary for efficient suppression of effector T cells proliferation and cytokine production, especially when tested in the presence of exogenous IL-1β.
Conclusion: We propose that the ability of Tregs to produce IL-1RII provides a decoy strategy to ensure regulation by modulating production of proinflammatory cytokines.  As Treg cells present at the site of inflammation have important role in modulating the immune response, our data provide an important additional mechanism by which Treg cells ensure effective regulation in a proinflammatory microenvironment.