IL-4-induced gene 1 maintains high Tob1 expression which contributes to TCR unresponsiveness in human T helper 17 cells
Santarlasci, Veronica ; Maggi, Laura ; Capone, Manuela ; et al. ; - ASI Sponsor
Jan - 2013

journal : European Journal of Immunology

Volume : 44 ; Issue : 3
type: Article Journal

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 anti-proliferative 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 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.

keywords :