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Infection and Immunity, June 2003, p. 3131-3137, Vol. 71, No. 6
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.6.3131-3137.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Critical Contribution of CD28-CD80/CD86 Costimulatory Pathway to Protection from Trypanosoma cruzi Infection

Yasushi Miyahira,1* Masaharu Katae,1,2 Seiki Kobayashi,3 Tsutomu Takeuchi,3 Yoshinosuke Fukuchi,2 Ryo Abe,4 Ko Okumura,5 Hideo Yagita,5 and Takashi Aoki1

Department of Molecular and Cellular Parasitology,1 Department of Respiratory Medicine,2 Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421,5 Department of Tropical Medicine and Parasitology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582,3 Division of Immunobiology, Research Institutes of Biological Sciences, Science University of Tokyo, 2669 Yamazaki, Noda City, Chiba 278-0022, Japan4

Received 23 December 2002/ Returned for modification 6 February 2003/ Accepted 22 February 2003

The CD28-CD80/CD86-mediated T-cell costimulatory pathway has been variably implicated in infectious immunity. In this study, we investigated the role of this costimulatory pathway in resistance to Trypanosoma cruzi infection by using CD28-deficient mice and blocking antibodies against CD80 and CD86. CD28-deficient mice exhibited markedly exacerbated T. cruzi infection, as evidenced by unrelenting parasitemia and 100% mortality after infection with doses that are nonlethal in wild-type mice. The blockade of both CD80 and CD86 by administering specific monoclonal antibodies also exacerbated T. cruzi infection in wild-type mice. Splenocytes from T. cruzi-infected, CD28-deficient mice exhibited greatly impaired gamma interferon production in response to T. cruzi antigen stimulation in vitro compared to those from infected wild-type mice. The induction of T. cruzi antigen-specific CD8+ T cells was also impaired in T. cruzi-infected, CD28-deficient mice. In addition to these defects in natural protection against T. cruzi infection, CD28-deficient mice were also defective in the induction of CD8+-T-cell-mediated protective immunity against T. cruzi infection by DNA vaccination. These results demonstrate, for the first time, a critical contribution of the CD28-CD80/CD86 costimulatory pathway not only to natural protection against primary T. cruzi infection but also to DNA vaccine-induced protective immunity to Chagas' disease.

* Corresponding author. Mailing address: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Phone: 81-3-5802-1043. Fax: 81-3-5800-0476. E-mail: miyahira{at}med.juntendo.ac.jp.

Editor: W. A. Petri, Jr.

Infection and Immunity, June 2003, p. 3131-3137, Vol. 71, No. 6
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.6.3131-3137.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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