Protein kinase B/Akt signals impair Th17 differentiation and support natural regulatory T cell function and induced regulatory T cell formation.
Protein kinase B (PKB)/Akt signals control T cell proliferation and differentiation but their effect on the generation and function of regulatory T cells (Treg) and Th17 cells is not well understood. In this study, we show that elevated PKB signals antagonize the immunosuppressive effect of TGF-beta1 on cell size, CD25 and CD98 expression, and proliferation of CD3-stimulated naive CD4(+) T cells from wild-type and CD28-deficient mice. Conventional CD4(+) T cells expressing active PKB are less susceptible to suppression by natural regulatory T cells. Although PKB signals do not affect the development of natural regulatory T cells, they enhance their suppressor capacity. Upon TCR triggering and TGF-beta1 costimulation, wild-type and CD28-deficient CD4(+) T cells transgenic for PKB readily express Foxp3, thereby acquiring suppressor capacity. These effects of elevated PKB signals on T cell function involve a marked and sustained activation of STAT5 and Foxp3 and reduction in nuclear NFATc1 levels. In contrast, PKB signals impair TGF-beta1/IL-6-mediated differentiation of naive CD4(+) T cells into the Th17 lineage. This correlates with an increased signaling of ERK, STAT5, and STAT6. Finally, elevated PKB signals reduced the severity of experimental autoimmune encephalomyelitis in wild-type mice but induced experimental autoimmune encephalomyelitis in mice deficient for CD28. Altogether, these data indicate an important role of PKB signals on control of TGF-beta1-mediated T cell responses and, thereby, on tolerizing and inflammatory immune processes.
Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
Mandy
M
Pierau
Swen
S
Engelmann
Dirk
D
Reinhold
Thabo
T
Lapp
Burkhart
B
Schraven
Ursula H
UH
Bommhardt
D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D027261:Fusion Regulatory Protein-1 / Q000276:immunology / Q000378:metabolism; D006023:Glycoproteins / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein; D050778:NFATC Transcription Factors / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology* / Q000378:metabolism
D018106:CD28 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D027261:Fusion Regulatory Protein-1; D006023:Glycoproteins; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D063308:Myelin-Oligodendrocyte Glycoprotein; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D010446:Peptide Fragments; D050799:STAT5 Transcription Factor; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D053773:Transforming Growth Factor beta1; C445081:myelin oligodendrocyte glycoprotein (35-55); D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases