IL-10 Signaling in T Cells Modulates Costimulation-independent Activation and is Essential for Transplant Tolerance Induction
1Plastic Surgery, Johns Hopkins University, Baltimore, MD, 2Frimley Health NHS Foundation Trust, London, United Kingdom
Meeting: 2021 American Transplant Congress
Abstract number: 559
Keywords: Co-stimulation, Inflammation, T cell activation, Tolerance
Topic: Basic Science » Lymphocyte Biology: Signaling, Co-Stimulation, Regulation
Session Information
Session Name: Lymphocyte Biology: Signaling, Co-Stimulation, Regulation
Session Type: Poster Abstract
Session Date & Time: None. Available on demand.
Location: Virtual
*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.
To cite this abstract in AMA style:
Lozano MIglesias, Bibicheff D, Chicco M, Komin A, Brandacher G, Raimondi G. IL-10 Signaling in T Cells Modulates Costimulation-independent Activation and is Essential for Transplant Tolerance Induction [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/il-10-signaling-in-t-cells-modulates-costimulation-independent-activation-and-is-essential-for-transplant-tolerance-induction/. Accessed December 10, 2024.« Back to 2021 American Transplant Congress