STAT5 polarization promotes iTregs and suppresses human T-cell alloresponses while preserving CTL capacity

J Leukoc Biol. 2014 Feb;95(2):205-13. doi: 10.1189/jlb.0313154. Epub 2013 Sep 25.


Alloreactivity negatively influences outcomes of organ transplantation or HCT from allogeneic donors. Standard pharmacologic immune suppression impairs T-cell function and jeopardizes the beneficial reconstitution of Tregs. Murine transplantation models have shown that STAT3 is highly expressed in alloreactive T cells and may be therapeutically targeted. The influence and effects of STAT3 neutralization in human alloreactivity, however, remain to be elucidated. In this study, S3I-201, a selective small-molecule inhibitor of STAT3, suppressed human DC-allosensitized T-cell proliferation and abrogated Th17 responses. STAT3 blockade significantly enhanced the expansion of potent iTregs and permitted CD8(+) cytolytic effector function. Mechanistically, S3I-201 polarized the ratio of STAT phosphorylation in favor of STAT5 over STAT3 and also achieved a significant degree of Foxp3 demethylation among the iTregs. Conversely, selective impairment of STAT5 phosphorylation with CAS 285986-31-4 markedly reduced iTregs. STAT3 represents a relevant target for achieving control over human alloresponses, where its suppression facilitates STAT5-mediated iTreg growth and function.

Keywords: GVHD; allogeneic hematopoietic stem cell transplantation; alloreactivity.

Publication types

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

MeSH terms

  • Allografts / drug effects
  • Allografts / immunology*
  • Aminosalicylic Acids / pharmacology
  • Animals
  • Benzenesulfonates / pharmacology
  • Cell Polarity / immunology*
  • Cell Proliferation / drug effects
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Immune Tolerance / drug effects
  • Immune Tolerance / immunology*
  • Interleukin-2 / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • Phosphorylation / drug effects
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Staining and Labeling
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / cytology
  • Th17 Cells / drug effects
  • Th17 Cells / metabolism


  • Aminosalicylic Acids
  • Benzenesulfonates
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2
  • NSC 74859
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor