Antithymocyte globulin inhibits CD8⁺ T cell effector functions via the paracrine induction of PDL-1 on monocytes

Abstract

Antithymocyte globulins (ATG) are T cell depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with high risk of graft rejection. Previously described effects besides depletion of T cells suggest additional modes of action and identified further cellular targets. Here, we examined the transcriptional changes arising in immune cells from human blood after ex vivo stimulation with ATG on a single cell level to uncover additional mechanisms by which ATG regulates T cell activity and effector functions. Analysis of the paracrine factors present in plasma of ATG-treated whole blood revealed high levels of chemokines and cytokines including Interferon-γ (IFN-γ). Furthermore, we identify an increase of surface expression of programmed death ligand 1 (PDL-1) on monocytes mediated by the released paracrine factors. In addition, we show that this induction is dependent on activation of JAK/STAT signaling via binding of IFN-γ to Interferon-γ receptor 1 (IFN-γR1). Lastly, we demonstrate that the modulation of the immune-regulatory axis of Programmed cell death protein 1 (PD-1) on activated CD8+ T cells with PDL-1 found on monocytes mediated by ATG potently inhibits effector functions including proliferation and granzyme B release of activated T cells. Together our findings represent a novel mode of action by which ATG exerts its immunosuppressive effects.