Neutralization of IL-2 prevents acute GVHD while preserving GVL activity via regulating PD-L1/PD-1 signaling

Abstract

Abstract Acute gut graft versus host disease (GVHD) has a critical impact on the outcome of allogeneic hematopoietic cell transplantation (allo-HCT). Our recent studies indicate that IL-2 from donor CD4+ T cells make infiltrating T cells resistant to host-tissue PD-L1-mediated tolerance (Ni & Song et al: JCI 2017), but the mechanisms remain unclear. To tested whether in vivo neutralization of IL-2 early after allo-HCT differentially regulates PD-L1/PD-1 signaling in GVHD target tissues and lymphoid tissues, spleen and BM cells from C57BL/6 (H-2b) donors were transplanted into lethally irradiated wild-type (WT) or PD-L1−/− BALB/c (H-2d) recipients in the presence or absence of BCL1 leukemia/lymphoma cells. Recipients were treated with neutralizing anti-IL-2 mAb or control IgG. Administration of anti-IL-2 completely prevented gut GVHD while preserving GVL activity in WT recipients but not in PD-L1−/− recipients. This effect was associated with expansion of donor T cells in the lymphoid tissues (i.e. spleen and MLN) but reduction of donor T cells in the GVHD target tissues such as the gut. Prevention of GVHD resulted from increased donor T apoptosis, with increased expression of Fas but reduced expression of Bcl-XL. Residual T cells showed evidence of enhanced anergy/exhaustion and upregulated expression of FR4, CD73, KLRG1 and Eomes. Finally, prevention of GVHD was associated with inhibition of pAKT/mTOR pathway in a donor T cell PD-1-dependent and host tissue PD-L1-dependent manner. These results indicate that neutralizing IL-2 early after allo-HCT augments tolerance-induction through PD-1 signaling mediated by host PD-L1 in GVHD target tissues but not in lymphoid tissues, thereby preventing gut GVHD while preserving GVL effects.