STAT5 polarization promotes iTregs and suppresses human T-cell alloresponses while preserving CTL capacity. J Leukoc Biol 2014 Feb;95(2):205-13
Date
09/27/2013Pubmed ID
24068731Pubmed Central ID
PMC3896660DOI
10.1189/jlb.0313154Scopus ID
2-s2.0-84897026776 (requires institutional sign-in at Scopus site) 27 CitationsAbstract
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.
Author List
Betts BC, Veerapathran A, Pidala J, Yu XZ, Anasetti CAuthor
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllograftsAminosalicylic Acids
Animals
Benzenesulfonates
Cell Polarity
Cell Proliferation
Dendritic Cells
Forkhead Transcription Factors
Humans
Immune Tolerance
Interleukin-2
Lymphocyte Activation
Mice
Phosphorylation
STAT3 Transcription Factor
STAT5 Transcription Factor
Signal Transduction
Staining and Labeling
T-Lymphocytes, Cytotoxic
T-Lymphocytes, Regulatory
Th17 Cells
