IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells

Veronica Santarlasci, Laura Maggi, Alessio Mazzoni, Manuela Capone, Valentina Querci, Maria Caterina Rossi, Luca Beltrame, Duccio Cavalieri, Raffaele De Palma, Francesco Liotta, Lorenzo Cosmi, Enrico Maggi, Sergio Romagnani, Francesco Annunziato

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)654-661
Number of pages8
JournalEuropean Journal of Immunology
Volume44
Issue number3
DOIs
Publication statusPublished - 2014

Fingerprint

Th17 Cells
Interleukin-4
Genes
Cell Cycle
Th1 Cells
Interleukin-2
Up-Regulation
Interleukin-4 Receptors
Cyclin B
Cyclin A
Retinoic Acid Receptors
T-Lymphocyte Subsets
Gene Silencing
B-Lymphocytes

Keywords

  • Human Th17 cells
  • IL4I1
  • T cell cycle
  • Tob1

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Santarlasci, V., Maggi, L., Mazzoni, A., Capone, M., Querci, V., Rossi, M. C., ... Annunziato, F. (2014). IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells. European Journal of Immunology, 44(3), 654-661. https://doi.org/10.1002/eji.201344047

IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells. / Santarlasci, Veronica; Maggi, Laura; Mazzoni, Alessio; Capone, Manuela; Querci, Valentina; Rossi, Maria Caterina; Beltrame, Luca; Cavalieri, Duccio; De Palma, Raffaele; Liotta, Francesco; Cosmi, Lorenzo; Maggi, Enrico; Romagnani, Sergio; Annunziato, Francesco.

In: European Journal of Immunology, Vol. 44, No. 3, 2014, p. 654-661.

Research output: Contribution to journalArticle

Santarlasci, V, Maggi, L, Mazzoni, A, Capone, M, Querci, V, Rossi, MC, Beltrame, L, Cavalieri, D, De Palma, R, Liotta, F, Cosmi, L, Maggi, E, Romagnani, S & Annunziato, F 2014, 'IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells', European Journal of Immunology, vol. 44, no. 3, pp. 654-661. https://doi.org/10.1002/eji.201344047
Santarlasci, Veronica ; Maggi, Laura ; Mazzoni, Alessio ; Capone, Manuela ; Querci, Valentina ; Rossi, Maria Caterina ; Beltrame, Luca ; Cavalieri, Duccio ; De Palma, Raffaele ; Liotta, Francesco ; Cosmi, Lorenzo ; Maggi, Enrico ; Romagnani, Sergio ; Annunziato, Francesco. / IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells. In: European Journal of Immunology. 2014 ; Vol. 44, No. 3. pp. 654-661.
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