STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease

Immunity. 2012 Aug 24;37(2):209-22. doi: 10.1016/j.immuni.2012.05.027.


Acute graft-versus-host disease (GvHD) is a major cause of mortality in allogeneic bone marrow transplantation (BMT), for which administration of FoxP3(+) regulatory T (Treg) cells has been proposed as a therapy. However, the phenotypic stability of Treg cells is controversial, and STAT3-dependent cytokines can inhibit FoxP3 expression. We assessed whether the elimination of STAT3 in T cells could limit the severity of GvHD. We found STAT3 limited FoxP3(+) Treg cell numbers following allogeneic BMT by two pathways: instability of natural Treg (nTreg) cells and inhibition of induced Treg (iTreg) cell polarization from naive CD4(+) T cells. Deletion of STAT3 within only the nTreg cell population was not sufficient to protect against lethal GvHD. In contrast, transfer of STAT3-deficient naive CD4(+) T cells increased FoxP3(+) Treg cells post-BMT and prevented lethality, suggesting that the consequence of STAT3 signaling may be greater for iTreg rather than nTreg cells during GvHD.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Bone Marrow Transplantation / adverse effects
  • Bone Marrow Transplantation / immunology*
  • Chromatin Immunoprecipitation
  • Cytokines / metabolism
  • Disease Models, Animal
  • Flow Cytometry
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / prevention & control
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / immunology
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / transplantation


  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse