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Role of STAT3 in CD4⁺CD25⁺FOXP3⁺ Regulatory Lymphocyte Generation: Implications in Graft-versus-Host Disease and Antitumor Immunity¹

Jean-René Pallandre^*, Emilie Brillard^*, Gilles Créhange, Amandine Radlovic^*, Jean-Paul Remy-Martin^*, Philippe Saas^*, Pierre-Simon Rohrlich^*, Xavier Pivot^*,, Xiang Ling, Pierre Tiberghien^* and Christophe Borg^2,*,

^* Institut National de la Santé et de la Recherche Médicale U645, EFS Bourgogne Franche Comté, University of Franche-Comté, Besançon, France; CHU Jean Minjoz, Department of Radiotherapy, Besançon, France; Centre Hospitalo-Universitaire Jean Minjoz, Department of Medical Oncology, Besançon, France; and Section of Molecular Hematology and Therapy, Department of Bone Marrow Transplantation, University of Texas, MD Anderson Cancer Center, Houston, TX 77030

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 Tyr⁷⁰⁵ 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-β1, decreased FOXP3 expression, prevented the acquisition of suppressive functions and restored the ability of the converted lymphocytes to produce IL-2 and IFN-. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ J.-R.P. was supported by the Conseil Regional de Franche Comté, E.B. has received a fellowship from the Ligue Française Contre le Cancer, and A.R. was financed by a grant from the Conseil Scientifique of Etablissement Français du Sang (no. CS-2005-14). This work has also been supported by Institut National de la Santé et de la Recherche Médicale, the Ligue Contre le Cancer, Comité du Doubs.

² Address correspondence and reprint requests to Dr. Christophe Borg, Institut National de la Santé et de la Recherche Médicale U645, Boulevard Fleming, 25000 Besançon, France. E-mail address: christophe.borg{at}efs.sante.fr

³ Abbreviations used in this paper: Treg, regulatory T cell; GvHD, graft-vs-host disease; aGvHD, acute GvHD; Foxp3, forkhead box P3; siRNA, small interfering RNA; ALK, anaplastic lymphoma kinase; QRT-PCR, quantitative real-time PCR.

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