title: Protein kinase C-θ inhibits inducible regulatory T cell differentiation via an AKT-Foxo1/3a-dependent pathway.
abstract: Protein kinase C (PKC)-θ has been shown to be a critical TCR signaling molecule that promotes the activation and differentiation of naive T cells into inflammatory effector T cells. In this study, we demonstrate that PKC-θ-mediated signals inhibit inducible regulatory T cell (iTreg) differentiation via an AKT-Foxo1/3A pathway. TGF-β-induced iTreg differentiation was enhanced in PKC-θ(-/-) T cells or wild-type cells treated with a specific PKC-θ inhibitor, but was inhibited by the PKC-θ activator PMA, or by CD28 crosslinking, which enhances PKC-θ activation. PKC-θ(-/-) T cells had reduced activity of the AKT kinase, and the expression of a constitutively active form of AKT in PKC-θ(-/-) T cells restored the ability to inhibit iTreg differentiation. Furthermore, knockdown or overexpression of the AKT downstream targets Foxo1 and Foxo3a was found to inhibit or promote iTreg differentiation in PKC-θ(-/-) T cells accordingly, indicating that the AKT-Foxo1/3A pathway is responsible for the inhibition of iTreg differentiation of iTregs downstream of PKC-θ. We conclude that PKC-θ is able to control T cell-mediated immune responses by shifting the balance between the differentiation of effector T cells and inhibitory Tregs.
authors.affiliation: Division of Immunology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Fang
authors.forename: Ruiqing
authors.initials: R
authors.lastname: Wang
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006131:Growth Inhibitors / Q000172:deficiency / Q000502:physiology*; D007527:Isoenzymes / Q000172:deficiency / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000172:deficiency / Q000502:physiology*; D000074121:Protein Kinase C-theta; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology*
chemical_list: D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D006131:Growth Inhibitors; D007527:Isoenzymes; D051057:Proto-Oncogene Proteins c-akt; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta