Critical contribution of CD28-CD80/CD86 costimulatory pathway to protection from Trypanosoma cruzi infection.
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.
Miyahira
Yasushi
Y
Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. miyahira@med.juntendo.ac.jp
Katae
Masaharu
M
Kobayashi
Seiki
S
Takeuchi
Tsutomu
T
Fukuchi
Yoshinosuke
Y
Abe
Ryo
R
Okumura
Ko
K
Yagita
Hideo
H
Aoki
Takashi
T
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology*; D004198:Disease Susceptibility; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016052:Protozoan Vaccines / Q000276:immunology; D013154:Spleen / Q000166:cytology; D014349:Trypanosoma cruzi / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D016052:Protozoan Vaccines; D019444:Vaccines, DNA; D007371:Interferon-gamma