Tumor-induced CD11b+ Gr-1+ myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner

Tamar Kapanadze, José Medina-Echeverz, Jaba Gamrekelashvili, Jonathan M. Weiss, Robert H. Wiltrout, Veena Kapoor, Nga Hawk, Masaki Terabe, Jay A. Berzofsky, Michael P. Manns, Ena Wang, Francesco M. Marincola, Firouzeh Korangy, Tim F. Greten

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7 Citations (Scopus)


Immunosuppressive CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing (TB) mice. We studied hepatic MDSCs in two murine models of immune-mediated hepatitis. Unexpectedly, treatment of TB mice with Concanavalin A (Con A) or α-galactosylceramide resulted in increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels in comparison to tumor-free mice. Adoptive transfer of hepatic MDSCs into naïve mice exacerbated Con A induced liver damage. Hepatic CD11b+Gr-1+ cells revealed a polarized proinflammatory gene signature after Con A treatment. An IFN-γ-dependent upregulation of CD40 on hepatic CD11b+Gr-1+ cells along with an upregulation of CD80, CD86, and CD1d after Con A treatment was observed. Con A treatment resulted in a loss of suppressor function by tumor-induced CD11b+Gr-1+ MDSCs as well as enhanced reactive oxygen species (ROS)-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Con A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40-/- tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased ROS production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as proinflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner.

Original languageEnglish
Pages (from-to)1148-1158
Number of pages11
JournalEuropean Journal of Immunology
Issue number4
Publication statusPublished - 1 Apr 2015



  • CD40
  • Concanavalin A
  • Immune-mediated hepatitis
  • Myeloid-derived suppressor cells
  • Reactive oxygen species
  • α-Galactosylceramide

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Kapanadze, T., Medina-Echeverz, J., Gamrekelashvili, J., Weiss, J. M., Wiltrout, R. H., Kapoor, V., Hawk, N., Terabe, M., Berzofsky, J. A., Manns, M. P., Wang, E., Marincola, F. M., Korangy, F., & Greten, T. F. (2015). Tumor-induced CD11b+ Gr-1+ myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner. European Journal of Immunology, 45(4), 1148-1158. https://doi.org/10.1002/eji.201445093