IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells.
IL-2(-/-) mice develop autoimmunity despite having relatively normal numbers of regulatory T cells (Tregs). In contrast, we demonstrate that IL-2(-/-) x IL-15(-/-) and IL-2Rbeta(-/-) mice have a significant decrease in Treg numbers. Ectopic expression of foxp3 in a subset of CD4(+) T cells rescued Treg development and prevented autoimmunity in IL-2Rbeta(-/-) mice, suggesting that IL-2Rbeta-dependent signals regulate foxp3 expression in Tregs. Subsequent analysis of IL-2Rbeta-dependent signal transduction pathways established that the transcription factor STAT5 is necessary and sufficient for Treg development. Specifically, T cell-specific deletion of STAT5 prevented Treg development; conversely, reconstitution of IL-2Rbeta(-/-) mice with bone marrow cells expressing an IL-2Rbeta mutant that exclusively activates STAT5 restored Treg development. Finally, STAT5 binds to the promoter of the foxp3 gene suggesting that IL-2Rbeta-dependent STAT5 activation promotes Treg differentiation by regulating expression of foxp3.
Burchill
Matthew A
MA
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA. farra005@tc.umn.edu
Yang
Jianying
J
Vogtenhuber
Christine
C
Blazar
Bruce R
BR
Farrar
Michael A
MA
D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D001483:Base Sequence; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019409:Interleukin-15; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D050799:STAT5 Transcription Factor