Activation of Valpha14(+) natural killer T cells by alpha-galactosylceramide results in development of Th1 response and local host resistance in mice infected with Cryptococcus neoformans.
We examined the effect of alpha-galactosylceramide (alpha-GalCer) on the synthesis of gamma interferon (IFN-gamma) and local resistance in mice infected intravenously with Cryptococcus neoformans. The level of IFN-gamma in serum increased on day 3, reached a peak level on day 7, and decreased to the basal level on day 14 postinfection in mice treated with alpha-GalCer, while in vehicle-treated mice, no increase was detected at any time points except for a small increase on day 7. Such effects were not observed in NKT-KO mice. In CD4KO mice, minor synthesis of IFN-gamma was detected on day 3 in sera but was completely abolished by day 7. The alpha-GalCer-induced IFN-gamma production on day 3 was partially reduced in mice depleted of NK cells by treatment with anti-asialo-GM(1) antibody (Ab). Spleen cells obtained from infected and alpha-GalCer-treated mice on day 7 produced a large amount of IFN-gamma upon restimulation with live organisms, while only a marginal level of production was detected in splenocytes from infected and vehicle-treated mice. Such effects were abolished in CD4KO and NKT-KO mice. Finally, the fungal loads in the lungs and spleen on days 7 and 14 were significantly reduced in alpha-GalCer-treated mice compared to those in control mice. In NKT-KO mice, local resistance elicited by alpha-GalCer was completely abolished, although no obvious exacerbation of infection was detected. Furthermore, treatment with anti-IFN-gamma monoclonal Ab mostly abrogated the protective effect of this agent. Thus, our results indicated that activation of Valpha14(+) NKT cells resulted in an increased Th1 response and local resistance to C. neoformans through production of IFN-gamma.
Kawakami
K
K
The First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. kawakami@med.u-ryukyu.ac.jp
Kinjo
Y
Y
Yara
S
S
Koguchi
Y
Y
Uezu
K
K
Nakayama
T
T
Taniguchi
M
M
Saito
A
A
D000818:Animals; D015704:CD4 Antigens / Q000502:physiology; D003453:Cryptococcosis / Q000276:immunology*; D005699:Galactosylceramides / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008168:Lung / Q000382:microbiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000382:microbiology; D018417:Th1 Cells / Q000276:immunology*
D015704:CD4 Antigens; D005699:Galactosylceramides; D015847:Interleukin-4; D007371:Interferon-gamma