Upregulation of Foxp3 expression in mouse and human Treg is IL-2/STAT5 dependent: implications for the NOD STAT5B mutation in diabetes pathogenesis.
Regulatory T cells (Treg), characterized as CD4(+)/CD25(+hi) T cells, are critical for sustaining and promoting immune tolerance. Treg are highly dependent on IL-2 and IL-2 signaling to maintain their numbers and function and interruption of this pathway promotes autoimmunity. The transcription factor, Foxp3, is also required for Treg function as defective Foxp3 promotes autoimmunity in both mice and humans. We previously reported a point mutation in the DNA-binding domain of the NOD STAT5B gene that limits DNA binding when compared to wild-type STAT5 mice. Based on the presence of five STAT5B consensus sequences in the Foxp3 promotor, we hypothesized a critical linkage between IL-2 signaling/STAT5B and Foxp3 expression in Treg. Our data show IL-2 activates long-form (LF) STAT5 and sustains Foxp3 expression in Treg. In contrast, CD4(+)/CD25(-) T cells do not active LF STAT5 and do not express Foxp3 under the same conditions. In addition, blocking LF STAT5 activation with a Jak inhibitor (AG-490) significantly reduced Foxp3 expression in Treg. Examination of human Treg using flow cytometry and intracellular staining for Foxp3 expression likewise demonstrates that IL-2 maintains Foxp3 expression through LF STAT5 signaling. These studies reveal a critical link between IL-2 mediated JAK-STAT5 signaling and the maintenance of Foxp3 expression in Treg of mice and humans.
Murawski
Matthew R
MR
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA.
Litherland
Sally A
SA
Clare-Salzler
Michael J
MJ
Davoodi-Semiromi
Abdoreza
A
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000209:etiology* / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D050799:STAT5 Transcription Factor / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*; D015854:Up-Regulation
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human