Smad-dependent cooperative regulation of interleukin 2 receptor alpha chain gene expression by T cell receptor and transforming growth factor-beta.
The interleukin 2 receptor alpha chain (IL-2Ralpha) is a component of high affinity IL-2 receptors and thus critically regulates T cell growth and other lymphoid functions. Five positive regulatory regions together control lineage-restricted and activation-dependent IL-2Ralpha induction in response to antigen and IL-2. We now show that TGF-beta cooperates with T cell receptor (TCR) signaling to increase IL-2Ralpha gene expression. Moreover, we identify a sixth positive regulatory region that regulates IL-2Ralpha expression in cells treated with anti-CD3 + anti-CD28 as well as TGF-beta and show that this region contains binding sites for Smad3, AP-1, and cAMP-responsive element-binding protein/ATF proteins. The importance of Smad complexes is indicated by impaired IL-2Ralpha induction by TGF-beta in CD4+ T cells from both Smad3-/- and Smad4-/- mice. Thus, we have identified a novel positive regulatory region in the IL-2Ralpha gene that mediates TGF-beta-dependent induction of the gene. These findings have implications related to IL-2Ralpha expression on activated T cells and regulatory T cells.
Kim
Hyoung-Pyo
HP
Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1674, USA.
Kim
Byung-Gyu
BG
Letterio
John
J
Leonard
Warren J
WJ
D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D005786:Gene Expression Regulation; D053645:Interleukin-2 Receptor alpha Subunit; D051379:Mice; D008810:Mice, Inbred C57BL; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*
C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D018123:Receptors, Interleukin; D051785:Smad Proteins; D016212:Transforming Growth Factor beta