Antithymocyte Globulin Inhibits CD8(+) T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes

卷:12

Article

关键词: IN-VITRO;    PD-1;    THYMOGLOBULIN;    ACTIVATION;    LYMPHOCYTES;    RECEPTORS;    TOLERANCE;    PATHWAY;    MECHANISMS;    CYTOSCAPE;   

DOI  :  10.3390/cells12030382

来源: SCIE

【 摘 要 】

Background: Antithymocyte globulins (ATG) are T cell-depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with a high risk of graft rejection. Previously described effects besides the depletion of T cells have suggested additional modes of action and identified further cellular targets. Methods: We examined the transcriptional changes arising in immune cells from human blood after ex vivo stimulation with ATG at the single-cell level to uncover additional mechanisms by which ATG regulates T cell activity and effector functions. Findings: Analysis of the paracrine factors present in the plasma of ATG-treated whole blood revealed high levels of chemokines and cytokines, including interferon-gamma (IFN-gamma). Furthermore, we identified an increase in the surface expression of the programmed death ligand 1 (PDL-1) on monocytes mediated by the released paracrine factors. In addition, we showed that this induction is dependent on the activation of JAK/STAT signaling via the binding of IFN-gamma to interferon-gamma receptor 1 (IFN-gamma R1). Lastly, we demonstrated that the modulation of the immune regulatory axis of programmed cell death protein 1 (PD1) on activated CD8(+) T cells with PDL-1 found on monocytes mediated by ATG potently inhibits effector functions including the proliferation and granzyme B release of activated T cells. Interpretation: Together, our findings represent a novel mode of action by which ATG exerts its immunosuppressive effects.