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