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African Trypanosomiasis: Naturally Occurring Regulatory T Cells Favor Trypanotolerance by Limiting Pathology Associated with Sustained Type 1 Inflammation¹

Martin Guilliams^*,, Guillaume Oldenhove, Wim Noel^*,, Michel Hérin^¶, Lea Brys^*,, Patrizia Loi, Véronique Flamand, Muriel Moser, Patrick De Baetselier^*, and Alain Beschin^2,*,

^* Department of Molecular and Cellular Interactions, Vlaams Instituut voor Biotechnologie, and Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussel, Belgium; Institut de Biologie et Médecine Moléculaires, and Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium; and ^¶ Cell and Tissue Laboratory, Unité de Recherche en Physiologie Moléculaire, Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium

Tolerance to African trypanosomes requires the production of IFN- in the early stage of infection that triggers the development of classically activated macrophages controlling parasite growth. However, once the first peak of parasitemia has been controlled, down-regulation of the type 1 immune response has been described. In this study, we have evaluated whether regulatory T cells (Tregs) contribute to the limitation of the immune response occurring during Trypanosoma congolense infection and hereby influence the outcome of the disease in trypanotolerant C57BL/6 host. Our data show that Foxp3⁺ Tregs originating from the naturally occurring Treg pool expanded in the spleen and the liver of infected mice. These cells produced IL-10 and limited the production of IFN- by CD4⁺ and CD8⁺ effector T cells. Tregs also down-regulated classical activation of macrophages resulting in reduced TNF- production. The Treg-mediated suppression of the type 1 inflammatory immune response did not hamper parasite clearance, but was beneficial for the host survival by limiting the tissue damages, including liver injury. Collectively, these data suggest a cardinal role for naturally occurring Tregs in the development of a trypanotolerant phenotype during African trypanosomiasis.

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, in frame of an Interuniversity Attraction Pole Program, by grants from the Institute for Promotion of Innovation by Science and Technology in Flanders-Vlaanderen for Generisch Basisonderzoek aan de Universiteiten and by the fund for Scientific Research in Flanders-Vlaanderen. M.G., and G.O. are recipients of a fellowship from Scientific Research in Flanders-Vlaanderen, the Institute for Promotion of Innovation by Science and Technology in Flanders-Vlaanderen, and Fonds National de la Recherche Scientifique-Télévie. M.M. is a senior research associate from Fonds National de la Recherche Scientifique.

² Address correspondence and reprint requests to Dr. Alain Beschin, Vlaams Instituut voor Biotechnologie, Department of Molecular and Cellular Interactions, Vrije Universiteit Brussel, Laboratory of Cellular and Molecular Immunology, 1050 Brussel, Belgium. E-mail address: abeschin{at}vub.ac.be

³ Abbreviations used in this paper: Treg, regulatory T cell; KO, knockout; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

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