Role of STAT3 in CD4+CD25+FOXP3+ regulatory lymphocyte generation: implications in graft-versus-host disease and antitumor immunity.

Jean-René Pallandre 1 Emilie Brillard 2 Gilles Créhange 2 Amandine Radlovic 2 Jean-Paul Remy-Martin 1 Philippe Saas 1 Pierre-Simon Rohrlich 1 Xavier Pivot 1, 3 Xiang Ling 4 Pierre Tiberghien 1 Christophe Borg 1, 3
1 HOTE GREFFON - Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098)
2 Service de radiothérapie
3 Service d'oncologie Médicale
4 Section of Molecular Hematology and Therapy
Abstract : Immunological tolerance is maintained by specialized subsets of T cells including CD4(+)CD25(+)FOXP3(+) regulatory cells (Treg). Previous studies established that Treg thymic differentiation or peripheral conversion depend on CD28 and Lck signaling. Moreover, foxp3 gene transfer in murine CD4(+)CD25(-) T lymphocytes results in the acquisition of suppressive functions. However, molecular pathways leading to FOXP3 expression remain to be described. In this study, we investigated the molecular events driving FOXP3 expression. We demonstrated that CD28 activation in CD4(+)CD25(-) T lymphocytes leads to STAT3 Tyr(705) phosphorylation in an Lck-dependent manner. STAT3 neutralization during naive peripheral CD4(+)CD25(-) T cell conversion into Treg through costimulation with TCR/CD28 and TGF-beta1, decreased FOXP3 expression, prevented the acquisition of suppressive functions and restored the ability of the converted lymphocytes to produce IL-2 and IFN-gamma. Furthermore, we observed that STAT3 ablation using small interfering RNA strategies inhibited FOXP3 expression and suppressive functions among naturally differentiated CD4(+)CD25(+) T lymphocytes, suggesting a direct role of STAT3 in Treg phenotype and function maintenance. CD4(+)CD25(+) T lymphocytes transduced with specific STAT3 small interfering RNA were devoid of suppressive functions and failed to control the occurrence of acute graft-vs-host disease. Finally, STAT3 inhibition in CD4(+) lymphocytes enhanced the anti-tumor immunity conferred by a lymphocyte adoptive transfer. In summary, our findings determine that STAT3 is critical in the molecular pathway required for FOXP3 expression. STAT3 modulation should be taken into account when assessing how regulatory T cells contribute to inflammatory diseases and tumor immunosurveillance.
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Article dans une revue
Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2007, 179 (11), pp.7593-604
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http://www.hal.inserm.fr/inserm-00479712
Contributeur : Philippe Saas <>
Soumis le : dimanche 2 mai 2010 - 12:43:37
Dernière modification le : lundi 9 juillet 2018 - 13:12:02

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  • HAL Id : inserm-00479712, version 1
  • PUBMED : 18025205

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UNIV-FCOMTE | UMR645

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Jean-René Pallandre, Emilie Brillard, Gilles Créhange, Amandine Radlovic, Jean-Paul Remy-Martin, et al.. Role of STAT3 in CD4+CD25+FOXP3+ regulatory lymphocyte generation: implications in graft-versus-host disease and antitumor immunity.. Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2007, 179 (11), pp.7593-604. 〈inserm-00479712〉

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