Abstract
BackgroundAgonist antibodies against CD137 (4–1BB) on T lymphocytes are used to increase host anti-tumor immunity, but often leading to severe liver injury in treated mice or in patients during clinical trials. Interleukin-6 (IL-6) has been reported to protect hepatocyte death, but the role of IL-6 in protecting chronic T cell-induced liver diseases is not clearly defined due to lack of relevant animal models. We aimed to define the role of IL-6 in CD8+ T cell-mediated liver injury induced by a CD137 agonistic mAb (clone 2A) in mice.Methods/Principal FindingsWe expressed IL-6 in the liver by hydrodynamic gene delivery in mice treated with 2A or control mAb and studied how IL-6 treatment affected host immunity and T cell-mediated liver injury. We found that ectopic IL-6 expression in the liver elevated intrahepatic leukocyte infiltration but prevented CD8+ T cell-mediated liver injury. In IL-6 treated mice, CD8+ T cells proliferation and IFN-γ expression were inhibited in the liver. We discovered that IL-6 increased accumulation of Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) in the liver and spleen. These MDSCs had the ability to inhibit T cells proliferation and activation. Finally, we showed that the MDSCs were sufficient and essential for IL-6-mediated protection of anti-CD137 mAb-induced liver injury.Conclusions/SignificanceWe concluded that IL-6 induced Gr-1+CD11b+ MDSCs in the liver to inhibit T cell-mediated liver injury. The findings have defined a novel mechanism of IL-6 in protecting liver from CD8+ T cell-mediated injury.
Highlights
Hepatitis or liver inflammation is a common disease, mainly caused by hepatitis B or C viruses, alcohol, and various chemical agents
We showed that these myeloid cells were sufficient and critical in IL-6-mediated suppression of T cell-mediated liver injury
Agonist CD137 mAb treatment has been shown to lead to CD8+ T cell-mediated liver injury in both mouse and human patients
Summary
Hepatitis or liver inflammation is a common disease, mainly caused by hepatitis B or C viruses, alcohol, and various chemical agents. Treatment with an agonistic anti-CD137 antibody (clone 2A) in mice can cause CD8+ T celldependent tumor rejection and virus clearance [5,6]. A single 2A treatment triggers hepatic infiltration and activation of CD8+ T cells, and CD8+ T cell-derived IFN-c plays a central role in the liver injury[7]. Agonist antibodies against CD137 (4–1BB) on T lymphocytes are used to increase host anti-tumor immunity, but often leading to severe liver injury in treated mice or in patients during clinical trials. Interleukin-6 (IL-6) has been reported to protect hepatocyte death, but the role of IL-6 in protecting chronic T cell-induced liver diseases is not clearly defined due to lack of relevant animal models. We aimed to define the role of IL-6 in CD8+ T cell-mediated liver injury induced by a CD137 agonistic mAb (clone 2A) in mice
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