*Purpose: Induction of long term transplant survival by “costimulation blockade” (CoB) is achieved through deletion of abortively activated alloreactive T cells and generation of graft protective regulatory T cells (Tregs). However, establishment of tolerance can be impaired by acute inflammatory responses. We and others recently revealed new interrelations between inflammatory cytokines and interleukin 10 (IL-10) that alter the signaling outcome of the latter. In this study we investigated the role of IL-10 during transplant tolerance induction.

*Methods: Full mismatch Balb/c into C57BL/6 (B6), or into B6 expressing in T cells a dominant negative IL-10R (DN), skin transplant recipients received a peri-transplant regimen based on donor specific infusion and anti-CD154 mAb (MR-1) +/- blocking a-IL-10R mAb. Rested-effector cells were generated in vitro via polyclonal activation of naïve T cells followed by resting.

*Results: The systemic blockade of IL-10R during CoB administration revealed that IL-10 signaling is essential for the regulation of alloreactivity (transplant survival: MST 105d with CoB vs 47d with a-IL-10R). In DN mice, extended graft survival could not be promoted by CoB (MST 30d) revealing an unexpected important direct modulation of T cells by IL-10. This accelerated rejection correlated with increased production of TNF-a, IFN-g and IL-17A by T cells, in comparison to B6 control recipients. We then investigated the direct role of IL-10 in modulating T cell functions. In experiments with rested-effector cells, the presence of IL-10 did not reduce their effector functions (cytokine secretion) after re-stimulation nor their signaling threshold. IL-10 did not alter the expression level of important checkpoint receptors either. What we discovered is that IL-10 can neutralize the poorly investigated effect of TLR-mediated (CD28 independent) costimulation of memory and effector T cells. We have an ongoing RNAseq analysis to decipher this novel mechanism at the molecular level.

*Conclusions: Overall, these results highlight the importance of IL-10 signaling for the therapeutic efficacy of CoB. Integrated with the “plasticity” of IL-10 from recent reports, they could explain why past attempts to use IL-10 to prevent allograft rejection were met with contradictory results. A better understanding of the effects of this cytokine on T cells will reveal targets of strategies to preserve its regulatory activity and ultimately sustain the clinical efficacy of CoB.

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