Active protein kinase B regulates TCR responsiveness by modulating cytoplasmic-nuclear localization of NFAT and NF-kappa B proteins.
T cell activation leads to the induction of the transcription factors of the NFAT and NF-kappa B families, important regulators of T cell activation and function. In this study we demonstrate that TCR/CD3-stimulated T cells from mice expressing a constitutively active form of protein kinase B (myr PKB alpha) lack significant nuclear accumulation/shuttling of NFATc1 and NFATp as well as NF-kappa Bp65 and RelB proteins. Notably, despite this deficit in nuclear NFAT and NF-kappa B proteins, myr PKB T cells show lower activation threshold for proliferation, enhanced cell cycle progression and increased production of Th1 and Th2 cytokines similar to signals provided by CD28 costimulation. The enhanced T cell response correlates with increased expression of cyclins D3 and B1 and cytokine-induced Src homology 2 protein, and inactivation of the forkhead transcription factor FKHR. In addition, coimmunoprecipitation studies indicate a direct regulation of NFATc1 by active PKB. Together, our results demonstrate that the positive regulatory role of myr PKB on TCR responsiveness, subsequent cell division, and effector function is linked to a negative regulatory mechanism on the nuclear accumulation/shuttling of NFAT and NF-kappa B proteins.
Patra
Amiya K
AK
Institute of Virology and Immunobiology, University of Würzburg, Wuerzburg, Germany.
Na
Shin-Young
SY
Bommhardt
Ursula
U
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002467:Cell Nucleus / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050778:NFATC Transcription Factors; D019913:Nuclear Localization Signals / Q000378:metabolism; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D014157:Transcription Factors; D016572:Cyclosporine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt