We recently demonstrated that human T helper (Th) 17 cells, unlike Th1 cells, do not proliferate in response to T-cell receptor stimulation, mainly because of their reduced capacity to produce and respond to IL-2. In this study we show that their lower responsiveness to IL-2 is due to the selective expression of Musculin (MSC), a member of the basic helix-loop-helix transcription factors. We show that MSC expression in human Th17 cells is retinoic acid orphan receptor (ROR)γt-dependent, and allows the up-regulation of PPP2R2B, a regulatory member of the protein phosphatase 2A (PP2A) enzyme. High PPP2R2B levels in human Th17 cells were responsible for the reduced STAT5B Ser-193 phosphorylation upon IL-2 signalling and, therefore, impaired STAT5B DNA binding and transcriptional activity on IL-2 target genes. PP2A, observed in Th17 cells, controls also STAT3, dephosphorylating Ser727, thus increasing its activity which plays a crucial role in Th17 development and/or maintenance. Thus, our findings identify an additional mechanism responsible for the limited expansion of human Th17 cells, and could provide a further explanation for the rarity of these cells in inflamed tissues. This article is protected by copyright. All rights reserved.

Musculin inhibits human T helper 17 cell response to interleukin 2 by controlling STAT5B activity / Santarlasci, Veronica; Mazzoni, Alessio; Capone, Manuela; Rossi, MARIA CATERINA; Maggi, Laura; Montaini, Gianni; Rossettini, Beatrice; Cimaz, Rolando; Ramazzotti, Matteo; Barra, Giusi; De Palma, Raffaele; Maggi, Enrico; Liotta, Francesco; Cosmi, Lorenzo; Romagnani, Sergio; Annunziato, Francesco. - In: EUROPEAN JOURNAL OF IMMUNOLOGY. - ISSN 0014-2980. - ELETTRONICO. - (2017), pp. 0-0. [10.1002/eji.201746996]

Musculin inhibits human T helper 17 cell response to interleukin 2 by controlling STAT5B activity

SANTARLASCI, VERONICA;MAZZONI, ALESSIO;CAPONE, MANUELA;ROSSI, MARIA CATERINA;MAGGI, LAURA;MONTAINI, GIANNI;ROSSETTINI, BEATRICE;CIMAZ, ROLANDO;RAMAZZOTTI, MATTEO;MAGGI, ENRICO;LIOTTA, FRANCESCO;COSMI, LORENZO;ROMAGNANI, SERGIO;ANNUNZIATO, FRANCESCO
2017

Abstract

We recently demonstrated that human T helper (Th) 17 cells, unlike Th1 cells, do not proliferate in response to T-cell receptor stimulation, mainly because of their reduced capacity to produce and respond to IL-2. In this study we show that their lower responsiveness to IL-2 is due to the selective expression of Musculin (MSC), a member of the basic helix-loop-helix transcription factors. We show that MSC expression in human Th17 cells is retinoic acid orphan receptor (ROR)γt-dependent, and allows the up-regulation of PPP2R2B, a regulatory member of the protein phosphatase 2A (PP2A) enzyme. High PPP2R2B levels in human Th17 cells were responsible for the reduced STAT5B Ser-193 phosphorylation upon IL-2 signalling and, therefore, impaired STAT5B DNA binding and transcriptional activity on IL-2 target genes. PP2A, observed in Th17 cells, controls also STAT3, dephosphorylating Ser727, thus increasing its activity which plays a crucial role in Th17 development and/or maintenance. Thus, our findings identify an additional mechanism responsible for the limited expansion of human Th17 cells, and could provide a further explanation for the rarity of these cells in inflamed tissues. This article is protected by copyright. All rights reserved.
2017
0
0
Goal 3: Good health and well-being for people
Santarlasci, Veronica; Mazzoni, Alessio; Capone, Manuela; Rossi, MARIA CATERINA; Maggi, Laura; Montaini, Gianni; Rossettini, Beatrice; Cimaz, Rolando; Ramazzotti, Matteo; Barra, Giusi; De Palma, Raffaele; Maggi, Enrico; Liotta, Francesco; Cosmi, Lorenzo; Romagnani, Sergio; Annunziato, Francesco
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1087991
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