STAT5 polarization promotes iTregs and suppresses human T-cell alloresponses while preserving CTL capacity.
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.
1.12902 Magnolia Drive, Tampa, FL 33612, USA. brian.betts@moffitt.org.
Brian C
BC
Betts
Anandharaman
A
Veerapathran
Joseph
J
Pidala
Xue-Zhong
XZ
Yu
Claudio
C
Anasetti
D064591:Allografts / Q000187:drug effects / Q000276:immunology*; D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D016764:Cell Polarity / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013194:Staining and Labeling; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; C520337:NSC 74859; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor
GVHD; allogeneic hematopoietic stem cell transplantation; alloreactivity