Enhanced Gamma Interferon Production through Activation of Valpha 14+ Natural Killer T Cells by alpha -Galactosylceramide in Interleukin-18-Deficient Mice with Systemic Cryptococcosis

doi:10.1128/IAI.69.11.6643-6650.2001

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Infection and Immunity, November 2001, p. 6643-6650, Vol. 69, No. 11
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.11.6643-6650.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Enhanced Gamma Interferon Production through Activation of V $alpha$ 14⁺ Natural Killer T Cells by $alpha$ -Galactosylceramide in Interleukin-18-Deficient Mice with Systemic Cryptococcosis

Kazuyoshi Kawakami,¹^,^* Yuki Kinjo,¹ Satomi Yara,¹ Kaori Uezu,¹ Yoshinobu Koguchi,¹ Masaki Tohyama,¹ Masato Azuma,¹ Kiyoshi Takeda,² Shizuo Akira,² and Atsushi Saito¹

First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa,¹ and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka,² Japan

Received 26 January 2001/Returned for modification 28 March 2001/Accepted 9 July 2001

We showed recently that activation of V $alpha$ 14⁺ natural killer T cells (NKT cells) by $alpha$ -galactosylceramide ( $alpha$ -GalCer) resultedin increased gamma interferon (IFN- $gamma$ ) production and host resistanceto intravenous infection with Cryptococcus neoformans. In otherstudies, interleukin-18 (IL-18) activated NKT cells in collaborationwith IL-12, suggesting the possible contribution of this cytokineto $alpha$ -GalCer-induced IFN- $gamma$ synthesis. Here we examined the roleof IL-18 in $alpha$ -GalCer-induced Th1 response by using IL-18KO micewith this infection. In these mice, levels of IFN- $gamma$ in serum andits synthesis in vitro by spleen cells stimulated with live organismswere not reduced, but rather enhanced, compared to those in wild-type(WT) mice, while such production was completely absent in IL-12KOmice. The enhanced production of IFN- $gamma$ correlated with increasedIL-12 synthesis but not with reduced production of IL-4, whichwas rather increased. IFN- $gamma$ synthesis in IL-18KO mice was abolishedby neutralizing anti-IL-12 antibody and significantly inhibitedby neutralization of endogenous IL-4 with a specific monoclonalantibody. In addition, administration of recombinant IL-4 significantlyenhanced the production of IFN- $gamma$ in WT mice. Finally, the enhancedproduction of IFN- $gamma$ in IL-18KO mice correlated with increasedhost defense against cryptococcal infection, as indicated by enhancementin $alpha$ -GalCer-related clearance of microorganisms. Our results indicatedthat in IL-18KO mice, IFN- $gamma$ synthesis was enhanced through overproductionof IL-12 and IL-4 after intravenous infection with C. neoformansand a ligand-specific activation of V $alpha$ 14⁺ NKTcells.

^* Corresponding author. Mailing address: The First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus,207 Uehara, Nishihara, Okinawa 903-0215, Japan. Phone: 81(98)895-1144. Fax: 81(98) 895-1414. E-mail: kawakami{at}med.u-ryukyu.ac.jp.

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Enhanced Gamma Interferon Production through Activation of V14+ Natural Killer T Cells by -Galactosylceramide in Interleukin-18-Deficient Mice with Systemic Cryptococcosis

Enhanced Gamma Interferon Production through Activation of V $alpha$ 14⁺ Natural Killer T Cells by $alpha$ -Galactosylceramide in Interleukin-18-Deficient Mice with Systemic Cryptococcosis