Abstract
Regulation of the extent of immune responses is a requirement to maintain self-tolerance and limit inflammatory processes. CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells play a role in regulation. The Foxp3 transcription factor is considered a dominant regulator for Treg cell development and function. Foxp3 function itself is directly regulated by multiple posttranslational modifications that occur in response to various external stimuli. The Foxp3 protein is a component of several dynamic macromolecular regulatory complexes. The complexes change constituents over time and through different signals to regulate the development and function of regulatory T cells. Here we identified a mechanism regulating Foxp3 level and activity that operates through discrete phosphorylation. The Pim-2 kinase can phosphorylate Foxp3, leading to decreased suppressive functions of Treg cells. The amino-terminal domain of Foxp3 is modified at several sites by Pim-2 kinase. This modification leads to altered expression of proteins related to Treg cell functions and increased Treg cell lineage stability. Treg cell suppressive function can be up-regulated by either pharmacologically inhibiting Pim-2 kinase activity or by genetically knocking out Pim-2 in rodent Treg cells. Deficiency of Pim-2 activity increases murine host resistance to dextran sodium sulfate-induced colitis in vivo, and a Pim-2 small molecule kinase inhibitor also modified Treg cell functions. Our studies define a pathway for limiting the regulation of Foxp3 function because the Pim-2 kinase represents a potential therapeutic target for modulating the Treg cell suppressive activities in controlling immune responses.
Highlights
Foxp3 activity is regulated by various posttranslational modifications
Foxp3 function itself is directly regulated by multiple posttranslational modifications that occur in response to various external stimuli
Negligible expression of Pim-1 and of Pim-3 was noted. This result extends a previous study suggesting that Pim-2 is expressed in Treg cells [23]. Because both Pim-2 and Foxp3 are highly expressed in mammalian Treg cells, we investigated whether Pim-2 interacts with Foxp3
Summary
Foxp activity is regulated by various posttranslational modifications. Results: Pim-2 kinase phosphorylates the Foxp N-terminal domain and influences the Foxp level in vivo. Significance: Phosphorylation of Foxp by Pim-2 kinase negatively regulates Treg cell suppressive function and stability. The Pim-2 kinase can phosphorylate Foxp, leading to decreased suppressive functions of Treg cells. The amino-terminal domain of Foxp is modified at several sites by Pim-2 kinase. This modification leads to altered expression of proteins related to Treg cell functions and increased Treg cell lineage stability. Our studies define a pathway for limiting the regulation of Foxp function because the Pim-2 kinase represents a potential therapeutic target for modulating the Treg cell suppressive activities in controlling immune responses. FOXP3 has a unique proline rich amino-terminal domain that is required for its repressive transcriptional activity. It has been suggested that phosphatase PP1 activated by TNF␣ can dephosphorylate
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