title: IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells.
abstract: Human Th17 cells have a limited proliferative capacity compared to other T-cell subsets. We have shown that human Th17 cells display impaired IL-2 production due to IL-4-induced gene 1 (IL4I1) upregulation. Here, we show that in human Th17 cells, IL4I1 also maintains high levels of Tob1, a member of the Tob/BTG (B-cell traslocation gene) antiproliferative protein family, which prevents cell-cycle progression mediated by TCR stimulation. Indeed, Th17 cells exhibited higher levels of Tob1 than Th1 cells in both resting and TCR-activated conditions. Accordingly, the expression of positive regulators of the cell cycle (cyclin A, B, C, and E and Cdk2), as well as of Skp2, which promotes Tob1 degradation, was lower in Th17 cells than in Th1 cells. Tob1 expression in human Th17 cells correlated with both RAR (retinoic acid receptor)-related orphan receptor C (RORC) and IL4I1 levels. However, RORC was not directly involved in the regulation of Tob1 expression, whereas IL4I1 silencing in Th17 cells induced a substantial decrease of Tob1 expression. These data suggest that IL4I1 upregulation in human Th17 cells limits their TCR-mediated expansion not only by blocking the molecular pathway involved in the activation of the IL-2 promoter, but also by maintaining high levels of Tob1, which impairs entry into the cell cycle.
authors.affiliation: Department of Experimental and Clinical Medicine and DENOTHE Center, University of Florence, Florence, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Santarlasci
authors.forename: Laura
authors.initials: L
authors.lastname: Maggi
authors.forename: Alessio
authors.initials: A
authors.lastname: Mazzoni
authors.forename: Manuela
authors.initials: M
authors.lastname: Capone
authors.forename: Valentina
authors.initials: V
authors.lastname: Querci
authors.forename: Maria Caterina
authors.initials: MC
authors.lastname: Rossi
authors.forename: Luca
authors.initials: L
authors.lastname: Beltrame
authors.forename: Duccio
authors.initials: D
authors.lastname: Cavalieri
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Palma
authors.forename: Francesco
authors.initials: F
authors.lastname: Liotta
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cosmi
authors.forename: Enrico
authors.initials: E
authors.lastname: Maggi
authors.forename: Sergio
authors.initials: S
authors.lastname: Romagnani
authors.forename: Francesco
authors.initials: F
authors.lastname: Annunziato
mesh_terms: D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D050830:L-Amino Acid Oxidase / Q000378:metabolism*; D008954:Models, Biological; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D044786:S-Phase Kinase-Associated Proteins; C098669:TOB1 protein, human; D025521:Tumor Suppressor Proteins; C105158:IL4I1 protein, human; D050830:L-Amino Acid Oxidase
keywords: Human Th17 cells; IL4I1; T cell cycle; Tob1