Instability of Foxp3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease.

Abstract

PURPOSE:

Graft versus host disease (GVHD) is the major complication of allogeneic bone marrow transplantation (BMT) and limits the therapeutic efficacy of this modality. Although the role of natural T-regulatory cells (nTreg) in attenuating GVHD has been extensively examined, the ability of induced T-regulatory cells (iTreg) to mitigate GVHD is unknown. The purpose of this study was to examine the ability of in vitro and in vivo iTregs to abrogate GVHD.

EXPERIMENTAL DESIGN:

We examined the ability of in vitro differentiated and in vivo iTregs to reduce the severity of GVHD in a clinically relevant mouse model of BMT. The effect of blockade of interleukin (IL) 6 signaling on the efficacy of these Treg populations was also studied.

RESULTS:

In vitro differentiated iTregs fail to protect mice from lethal GVHD even when administered at high Treg:effector T-cell ratios. Lack of GVHD protection was associated with loss of Foxp3 expression and in vivo reversion of these cells to a proinflammatory phenotype characterized by secretion of IFN-γ. Phenotypic reversion could not be abrogated by blockade of IL-6 signaling or by in vitro exposure of iTregs to all-trans retinoic acid. In contrast, the in vivo induction of iTregs was significantly augmented by IL-6 blockade and this resulted in reduced GVHD.

CONCLUSION:

Instability of Foxp3 expression limits the utility of adoptively transferred iTregs as a source of cellular therapy for the abrogation of GVHD. Blockade of IL-6 signaling augments the ability of in vivo iTregs to prevent GVHD but has no effect on in vitro differentiated iTregs.

• Authors: Amy Beres, Richard Komorowski, Masahiko Mihara, William R Drobyski
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 12 Pg. 3969-83 (Jun 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21558402 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antibodies, Blocking
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Immunologic Factors
• Receptors, Interleukin-6
• Tretinoin

Topics

• Animals
• Antibodies, Blocking (immunology, pharmacology)
• Bone Marrow Transplantation (adverse effects)
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Regulation (immunology)
• Graft vs Host Disease (etiology, genetics, immunology, physiopathology)
• Immunologic Factors (immunology, pharmacology)
• Inflammation (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Phenotype
• Receptors, Interleukin-6 (antagonists & inhibitors, immunology)
• Signal Transduction (drug effects, immunology)
• T-Lymphocytes, Regulatory (drug effects, immunology)
• Tretinoin (immunology)