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Cutting Edge: Small Molecule CD40 Ligand Mimetics Promote Control of Parasitemia and Enhance T Cells Producing IFN- during Experimental Trypanosoma cruzi Infection¹

Mohammed Habib^*, Magali Noval Rivas^*, Mustapha Chamekh, Sébastien Wieckowski, Weimin Sun, Alberto Bianco, Nathalie Trouche, Olivier Chaloin, Hélène Dumortier, Michel Goldman^*, Gilles Guichard, Sylvie Fournel^2, and Bernard Vray^2,*

^* Laboratoire d’Immunologie Expérimentale and Laboratoire de Bactériologie Moléculaire Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium; and Centre National de la Recherche Scientifique, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d’Immunologie et Chimie Thérapeutiques, Strasbourg, France

Host resistance to Trypanosoma cruzi infection depends on a type 1 response characterized by a strong production of IL-12 and IFN-. Amplifying this response through CD40 triggering results in control of parasitemia. Two newly synthesized molecules (<3 kDa) mimicking trimeric CD40L (mini CD40Ls-1 and -2) bind to CD40, activate murine dendritic cells, and elicit IL-12 production. Wild-type but not CD40 knockout mice exhibited a sharp decrease of parasitemia and mortality when inoculated with T. cruzi mixed with miniCD40Ls. Moreover, the immunosuppression induced by T. cruzi infection was impaired in mice treated with miniCD40Ls, as shown by proliferation of splenic lymphocytes, percentage of CD8⁺ T cells, and IFN- production. Mice surviving T. cruzi infection in the presence of miniCD40L-1 were immunized against a challenge infection. Our results indicate that CD40L mimetics are effective in vivo and promote the control of T. cruzi infection by overcoming the immunosuppression usually induced by the parasites.

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 the Centre de Recherche Interuniversitaire en Vaccinologie (to M.H. and B.V.), by the Centre National de la Recherche Scientifique, the "Ministère de la Recherche" (Action Concertee Incitative "Jeunes Chercheurs") and "La Ligue contre le Cancer, Région Alsace" (to G.G., N.T., and S.F.). S.W. and W.S. were supported, respectively, by a grant from the "Ministère de la Recherche" and the "Fondation pour la Recherche Médicale."

² Address correspondence and reprint requests to Prof. Bernard Vray, Laboratoire d’Immunologie Expérimentale (CP 615), Faculté de Médecine, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Brussels, Belgium; E-mail address: bvray{at}ulb.ac.be or Prof. Sylvie Fournel, Centre National de la Recherche Scientifique, Institut de Biologie Moléculaire et Cellulaire, Laboratoire d’Immunologie et Chimie Thérapeutiques, Strasbourg, France; E-mail address: S.Fournel{at}ibmc.u-strasbg.fr

³ Abbreviations used in this paper: DC, dendritic cell; MPM, mouse peritoneal macrophage; SC, spleen cell.