Pim-2 Kinase Influences Regulatory T Cell Function and Stability by Mediating Foxp3 Protein N-terminal Phosphorylation.

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.

• Authors: Guoping Deng, Yasuhiro Nagai, Yan Xiao, Zhiyuan Li, Shujia Dai, Takuya Ohtani, Alison Banham, Bin Li, Shiaw-Lin Wu, Wayne Hancock, Arabinda Samanta, Hongtao Zhang, Mark I Greene
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 33 Pg. 20211-20 (Aug 14 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 25987564 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Pim2 protein, mouse
• Proto-Oncogene Proteins
• Protein Serine-Threonine Kinases

Topics

• Amino Acid Sequence
• Animals
• Mice
• Mice, Knockout
• Molecular Sequence Data
• Phosphorylation
• Protein Serine-Threonine Kinases (chemistry, genetics, metabolism)
• Proto-Oncogene Proteins (chemistry, genetics, metabolism)
• T-Lymphocytes, Regulatory (immunology)