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* Departamento de Biología Molecular (Unidad asociada al Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Científicas) and
Departamento de Ciencias Medicas y Quirúrgicas, Universidad de Cantabria, Santander, Spain;
Division de Reumatología, Hospital Xeral-Calde, Lugo, Spain;
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland;
¶ Sección de Inmunología, Hospital Universitario Marqués de Valdecilla, Santander, Spain; and
|| Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain
Regulation of lymphocyte survival is essential for the maintenance of lymphoid homeostasis preventing the development of autoimmune diseases. Recently, we described a systemic lupus erythematosus associated with an IgA nephropathy in autoimmune-prone (NZW x C57BL/6)F1 overexpressing human Bcl-2 (hBcl-2) in B cells (transgenic (Tg) 1). In the present study, we analyze in detail a second line of hBcl-2 Tg mice overexpressing the transgene in all B cells and in a fraction of CD4+ and CD8+ T cells (Tg2). We demonstrate here that the overexpression of hBcl-2 in T cells observed in Tg2 mice is associated with a resistance to the development of lupus disease and collagen type II-induced arthritis in both (NZW x C57BL/6)F1 and (DBA/1 x C57BL/6)F1 Tg2 mice, respectively. The disease-protective effect observed in autoimmune-prone Tg2 mice is accompanied by an increase of peripheral CD4+CD25+ hBcl-2+ regulatory T cells (Tregs), expressing glucocorticoid-induced TNFR, CTLA-4, and FoxP3. Furthermore, the in vivo depletion of CD4+CD25+ Tregs in (DBA/1 x C57BL/6)F1 Tg2 mice promotes the development of a severe collagen type II-induced arthritis. Taken together, our results indicate that the overexpression of hBcl-2 in CD4+ T cells alters the homeostatic mechanisms controlling the number of CD4+CD25+ Tregs resulting in the inhibition of autoimmune diseases.
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 SAF2002-02624 and SAF2005-00811 from the Ministerio de Educación y Ciencia (Spain) and a grant from the Fundación Ramón Areces (to R.Me.); by Grant SAF2003-09772-C03-02 from the Ministerio de Educación y Ciencia (Spain) (to J.M.); by Grants PI050047 and PI020184 from the Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo (Spain) (to M.L.-H.); by Grant RTIC C03/03 from the Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo (Spain) (to R.Me. and M.L.H.); and by a grant from Swiss National Foundation (to S.I.). J.G. is a recipient of postdoctoral fellowships from the Universidad de Cantabria (Spain). E.T. has been a recipient of predoctoral fellowships from Ministerio de Educación y Ciencia (Formacion de Personal Universitario Program) and Fundación Marqués de Valdecilla (Spain).
2 J.M. and R.Me. share senior authorship.
3 Address correspondence and reprint requests to Dr. Ramón Merino, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Departamento de Biología Molecular, Facultad de Medicina, Universidad de Cantabria, Cardenal Herrera Oria s/n, 39011 Santander, Spain. E-mail address: merinor{at}unican.es
4 Abbreviations used in this paper: SLE, system lupus erythematosus; Treg, regulatory T cell; GITR, glucocorticoid-induced TNFR; hBcl-2, human Bcl-2; CIA, collagen type II-induced arthritis; Tg, transgenic; col-II, bovine collagen type II; PT, pertussis toxin; TU, titration unit; IgAN, IgA nephropathy; IC, immune complex; EAE, experimental autoimmune encephalomyelitis.
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