Rational regulation of alloreactive T cells (alloT) responses is the ideal goal of tolerance promoting therapies. However, our understanding of the factors and mechanisms that modulate the susceptibility of alloT to regulation is very limited. We and others have demonstrated recently that the ability of regulatory T cells (Treg) to suppress alloT is compromised in an inflamed environment. We hypothesise that inflammatory mediators, by contributing to the activation of alloT while reducing Treg activity, underlie the limited clinical effectiveness of tolerogenic regimens (e.g. CD28 blockade). We aimed to identify inflammatory mediators that lessen alloT regulation. We implemented a bio-informatic analysis to evaluate the secretion of 23 cytokines by maturing murine dendritic cells. This analysis suggested that IL-1Α and IL-1Β could parallel IL-6 in reducing the regulatory activity of Treg. Using a CFSE-based, in vitro mouse T cell activation system, we confirmed that both IL-1Α and Β exert a profound negative effect on inhibition of alloT activation by Treg. In a mouse model of inflammatory bowel disease based on adoptive transfer of T cells +/- Treg, Ab-mediated blockade of IL-6 signaling delayed disease development through a process dependent on the presence of Treg. By contrast, administration of IL-1R antagonist did not cause any delay in disease progression. IL-1 signaling, however, is complemented by the IL-1 family member IL-18 (through the common intracellular mediator Myd88). When Myd88-KO T cells where used in this model, we observed a significant delay of weight loss, corroborating the hypothesis that IL-1 and IL-18 have redundant modulatory function. Finally, we investigated the production of inflammatory cytokines following orthotopic vascularized composite (hind-limb) allotransplantation. IL-6, IL-1Α, IL-1Β, and particularly IL-18 accumulated at significant levels and for prolonged time in both the transplanted skin and muscle. These observations provide clear evidence that these cytokines play an important role in promoting the development of rejection, by antagonizing the regulation of alloT, and are necessary targets for therapeutic interventions.

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