*Purpose: Costimulation blockade (CoB)-based immunotherapy remains a very promising approach for better management of transplant recipients. Understanding the mechanisms that impact the efficacy of CoB is a necessary step toward translation into a clinically successful protocol. Integration of pro- and anti-inflammatory cues by T cells is now recognized to modulate their activation. We aimed at elucidating the role of direct IL-10 signaling in T cells in the outcome of CoB therapy.

*Methods: Balb/c skin was transplanted to wt C57BL/6 (B6) or to B6 with T cells expressing a dominant negative IL-10 receptor which make them unresponsive to this cytokine (10R-DN). Recipients received peri-transplant donor specific infusion and three weekly anti-CD154 mAb administrations. Studies on effector T cells were conducted using in vitro activated polyclonal T cells that were then rested for 3 days.

*Results: Unmanipulated 10R-DN recipients rejected their transplant with dynamics identical to wt B6. However, differently from wt B6, graft survival in 10R-DN could not be promoted by CoB (MST 105d vs 30d in the latter) revealing an unexpected important direct effect of IL-10 on T cells. This accelerated rejection correlated with increased production of TNF-a, IFN-g and IL-17A by T cells in spleen and draining lymphoid tissues of 10R-DN mice, in comparison to B6 recipients. Surprisingly, in vitro experiments of both TH differentiation and effectors reactivation showed that IL-10 did not significantly altered effector functions (cytokine secretion). Moreover, IL-10 did not alter the expression of important checkpoint receptors. We then tested if IL-10 could impact costimulation-independent T cell activation (recognized to afflict the efficacy of CoB). In vitro experiments clearly showed that IL-10 neutralizes the poorly investigated effect of TLR-mediated costimulation of naïve, effector, and memory T cells. We are now interested in deciphering the mechanisms behind such an important regulation.

*Conclusions: Overall, these results reveal a previously unappreciated role of IL-10 signaling in T cells as pre-requisite for the therapeutic efficacy of CoB. Merged with the recognized plasticity of IL-10 signaling, this observation opens a novel area of investigation that could reveal new “Achille’s Heels” in the successful implementation of CoB and suggest complementary interventions for the actuation of robust immunoregulation.

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