title: Transiently reduced PI3K/Akt activity drives the development of regulatory function in antigen-stimulated Naïve T-cells.
abstract: Regulatory T-cells (Tregs) are central for immune homeostasis and divided in thymus-derived natural Tregs and peripherally induced iTreg. However, while phenotype and function of iTregs are well known, a remarkable lack exists in knowledge about signaling mechanisms leading to their generation from naïve precursors in peripheral tissues. Using antigen specific naïve T-cells from mice, we investigated CD4+ CD25+ FoxP3- iTreg induction during antigen-specific T-cell receptor (TCR) stimulation with weak antigen presenting cells (APC). We show that early signaling pathways such as ADAM-17-activation appeared similar in developing iTreg and effector cells (Teff) and both initially shedded CD62-L. But iTreg started reexpressing CD62-L after 24 h while Teff permanently downmodulated it. Furthermore, between 24 and 72 hours iTreg presented with significantly lower phosphorylation levels of Akt-S473 suggesting lower activity of the PI3K/Akt-axis. This was associated with a higher expression of the Akt hydrophobic motif-specific phosphatase PHLPP1 in iTreg. Importantly, the lack of costimulatory signals via CD28 from weak APC was central for the development of regulatory function in iTreg but not for the reappearance of CD62-L. Thus, T-cells display a window of sensitivity after onset of TCR triggering within which the intensity of the PI3K/Akt signal controls entry into either effector or regulatory pathways.
authors.affiliation: University Duisburg-Essen, University Hospital, Institute for Experimental Immunology and Imaging, Essen, Germany.
authors.forename: Eloho
authors.initials: E
authors.lastname: Etemire
authors.forename: Marco
authors.initials: M
authors.lastname: Krull
authors.forename: Mike
authors.initials: M
authors.lastname: Hasenberg
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.forename: Matthias
authors.initials: M
authors.lastname: Gunzer
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation; D019041:L-Selectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D019041:L-Selectin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse; C000606463:Adam17 protein, mouse