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Infection and Immunity, April 1999, p. 1929-1934, Vol. 67, No. 4
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

CD40 Ligation Prevents Trypanosoma cruzi Infection through Interleukin-12 Upregulation

Damien Chaussabel,1 Frédérique Jacobs,1 Jan de Jonge,2 Marijke de Veerman,2 Yves Carlier,3 Kris Thielemans,2 Michel Goldman,1 and Bernard Vray1,*

Laboratoire d'Immunologie Expérimentale1 and Laboratoire de Parasitologie,3 Faculté de Médecine, Université Libre de Bruxelles, and Laboratorium Fysiologie, Faculteit Geneeskunde, Vrije Universiteit Brussel,2 Brussels, Belgium

Received 14 September 1998/Returned for modification 19 October 1998/Accepted 21 January 1999

Because of the critical role of the CD40-CD40 ligand (CD40L) pathway in the induction and effector phases of immune responses, we investigated the effects of CD40 ligation on the control of Trypanosoma cruzi infection. First, we observed that supernatants of murine spleen cells stimulated by CD40L-transfected 3T3 fibroblasts (3T3-CD40L transfectants) prevent the infection of mouse peritoneal macrophages (MPM) by T. cruzi. This phenomenon depends on de novo production of nitric oxide (NO) as it is prevented by the addition of N-nitro-L-arginine methyl ester, a NO synthase inhibitor. NO production requires interleukin (IL)-12-mediated gamma interferon (IFN-gamma ) and tumor necrosis factor alpha (TNF-alpha ) synthesis as demonstrated by inhibition experiments using neutralizing anti-IL-12, anti-IFN-gamma , and anti-TNF-alpha monoclonal antibodies (MAb). We found that an activating anti-CD40 MAb also directly stimulates IFN-gamma -activated MPM to produce NO and thereby to control T. cruzi infection. To determine the in vivo relevance of these in vitro findings, mice were injected with 3T3-CD40L transfectants or 3T3 control fibroblasts at the time of T. cruzi inoculation. We observed that in vivo CD40 ligation dramatically reduced both parasitemia and the mortality rate of T. cruzi-infected mice. A reduced parasitemia was still observed when the injection of 3T3-CD40L transfectants was delayed 8 days postinfection. It was abolished by injection of anti-IL-12 MAb. Taken together, these data establish that CD40 ligation facilitates the control of T. cruzi infection through a cascade involving IL-12, IFN-gamma , and NO.

* Corresponding author. Mailing address: Laboratoire d'Immunologie Expérimentale (CP 615), Faculté de Médecine, Université Libre de Bruxelles, route de Lennik, B-1070 Brussels, Belgium. Phone: 32-2-555.62.60. Fax: 32-2-555.63.60. E-mail: bvray{at}med.ulb.ac.be.

Infection and Immunity, April 1999, p. 1929-1934, Vol. 67, No. 4
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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