IL-10 Signaling in T Cells is Essential for Transplant Tolerance Induction

Abstract

Abstract Costimulation blockade (CoB)-based immunotherapy is a promising approach for transplant recipients yet to be realized. Elucidating which factors impact the efficacy of CoB is a necessary step to enable clinical applicability. In this regard, pro- and anti-inflammatory cytokines are being recognized as having an impact on T cell activation beyond effector differentiation. We then aimed at elucidating the role that direct IL-10 signaling in T cells has on the outcome of CoB. We employed a mouse skin transplt model were Balb/c skin was transplanted to wt C57BL/6 (B6) mice or to B6 with T cell-restricted expression of a dominant negative IL-10 receptor (10R-DN). Recipients received peri-transplant donor specific infusion and three weekly anti-CD154 mAb doses. 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 a novel and important effect of IL-10 on T cells. This accelerated rejection correlated with increased production of TNF-α, IFN-γ and IL-17 by T cells in draining lymphoid tissues. MLR experiments indicated that despite IL-10 signaling is not involved in the ability of anti-CD154 to modulate alloreactive T cell proliferation, absence of this pathway increased the differentiation of TH1 effector cells. Moreover, the same experiments indicated that lack of IL-10 signaling in T cells impaired induction of Tregs. Overall, our results reveal previously unappreciated roles of IL-10 signaling in T cells that represent potential “Achille’s Heels” in the successful implementation of CoB and suggest complementary interventions for the actuation of robust immunoregulation. Supported by a grant from JDRF (2-SRA-2016-304-S-B)