Pediatric liver transplant recipients with operational tolerance exhibit features of immune activation and exhaustion (TRAN3P.869)

Abstract

Abstract Experimental models describe immune exhaustion in liver transplant tolerance. It is not known if immune exhaustion is also occurs in clinical operational tolerance. We tested this in a cross-sectional cohort of pediatric liver transplant recipients with stable allograft function in the absence of immunosuppression (Operationally Tolerant, OT) in comparison to those Weaned off Immunosuppression (WI), continued on Maintenance Immunosuppression (MI) and Healthy Controls (HC). Results: In OT recipients, B cell frequencies (p <0.05) were increased and were enriched in both unswitched (p<0.005) and switched memory B cells (CD19+ IgM+ CD27+ and CD19+ IgG+ CD27+) (p<0.05) compard to MI. CD8 T cells in OT showed an increase in effector memory compared to MI (p<0.05). CD4 Treg frequencies were increased in OT compared to MI (p<0.0005). Both CD4 and CD8 T cells in OT showed an increase in cells expressing CD57, indicative of replicative senescence and these were enriched within CD4 central memory and CD8 effector memory when compared to MI (p<0.05). CD57+ T cells upregulated PD1 and 2B4, markers of exhaustion in OT compared to MI (p<0.05). Upon stimulation, IFNγ expression in CD4 T cells and IL-2 expression in CD8 T cells in OT were decreased compared to MI consistent with exhaustion. Moreover, OT showed decreased CD8 frequencies (p<0.05) and high PDL1 expression on monocytes (p<0.0005) suggesting that this population might contribute to T cell exhaustion in these recipients.