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In Vitro and In Vivo Down-Regulation of Regulatory T Cell Activity with a Peptide Inhibitor of TGF-β1¹

Lucía Gil-Guerrero^2,*, Javier Dotor^2,*, Inge Louise Huibregtse, Noelia Casares^*, Ana Belén López-Vázquez^*, Francesc Rudilla^*, José Ignacio Riezu-Boj^*, Jacinto López-Sagaseta, José Hermida, Sander Van Deventer, Jaione Bezunartea^*, Diana Llopiz^*, Pablo Sarobe^*, Jesús Prieto^*, Francisco Borrás-Cuesta^3,* and Juan José Lasarte^3,4,*

^* Center for Applied Medical Research, Division of Hepatology and Gene Therapy, and Division of Cardiovascular Sciences, University of Navarra, Pamplona, Spain; and Academic Medical Center, Center for Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands

Down-regulation of CD4⁺CD25⁺ regulatory T (Treg) cell function might be beneficial to enhance the immunogenicity of viral and tumor vaccines or to induce breakdown of immunotolerance. Although the mechanism of suppression used by Treg cells remains controversial, it has been postulated that TGF-β1 mediates their immunosuppressive activity. In this study, we show that P17, a short synthetic peptide that inhibits TGF-β1 and TGF-β2 developed in our laboratory, is able to inhibit Treg activity in vitro and in vivo. In vitro studies demonstrate that P17 inhibits murine and human Treg-induced unresponsiveness of effector T cells to anti-CD3 stimulation, in an MLR or to a specific Ag. Moreover, administration of P17 to mice immunized with peptide vaccines containing tumor or viral Ags enhanced anti-vaccine immune responses and improved protective immunogenicity against tumor growth or viral infection or replication. When CD4⁺ T cells purified from OT-II transgenic mice were transferred into C57BL/6 mice bearing s.c. EG.7-OVA tumors, administration of P17 improved their proliferation, reduced the number of CD4⁺Foxp3⁺ T cells, and inhibited tumor growth. Also, P17 prevented development of immunotolerance induced by oral administration of OVA by genetically modified Lactococcus lactis in DO11.10 transgenic mice sensitized by s.c. injection of OVA. These findings demonstrate that peptide inhibitors of TGF-β may be a valuable tool to enhance vaccination efficacy and to break tolerance against pathogens or tumor Ags.

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 This work was supported by grants from Fundación Mutua Madrileña and Gobierno de Navarra (to J.J.L.), by Grants SAF2007-61432 (to J.J.L.), SAF2004-01680 (to P.S.), and SAF2003-04751 (to F.B.-C.) from Ministerio de Educación y Ciencia, and by Unión Temporal de Empresas-proyecto Centro de Investigación Médica Aplicada.

² L.G.-G. and J.D. contributed equally to this work.

³ F.B.-C. and J.J.L. are senior authors on this work.

⁴ Address correspondence and reprint requests to Dr. Juan José Lasarte, Área de Hepatología y Terapia Génica, Centro de Investigación Médica Aplicada, Avenida Pío XII no. 55, 31008 Pamplona, Spain. E-mail address: jjlasarte{at}unav.es

⁵ Abbreviations used in this paper: Treg, regulatory T; TCd, cytotoxic T cell determinant; LAP, latency-associated peptide; HCV, hepatitis C virus; DTH, delayed-type hypersensitivity.