Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion

J Exp Med. 2016 Aug 22;213(9):1881-900. doi: 10.1084/jem.20151563. Epub 2016 Aug 15.


Donor CD4(+)Foxp3(+) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT [allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2- and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Female
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / prevention & control*
  • Hematopoietic Stem Cell Transplantation
  • Interleukin-2 / pharmacology
  • Mice
  • Mice, Inbred Strains
  • Myeloid-Derived Suppressor Cells / physiology
  • Receptors, Tumor Necrosis Factor, Type II / physiology*
  • T-Lymphocytes, Regulatory / immunology*


  • Interleukin-2
  • Receptors, Tumor Necrosis Factor, Type II

Associated data

  • PDB/1TNR
  • PDB/3ALQ