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Infection and Immunity, February 2005, p. 849-858, Vol. 73, No. 2
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.2.849-858.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Invariant V14 Chain NKT Cells Promote Plasmodium berghei Circumsporozoite Protein-Specific Gamma Interferon- and Tumor Necrosis Factor Alpha-Producing CD8⁺ T Cells in the Liver after Poxvirus Vaccination of Mice

Nuffield Department of Medicine, John Radcliffe Hospital,¹ Weatherall Institute of Molecular Medicine, Oxford University,⁵ The Wellcome Trust Center for Human Genetics, Oxford,³ Department of Biological Sciences, Imperial College London, London, United Kingdom,⁴ Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany,² RIKEN Research Center for Allergy/Immunology and Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chuoku, Chiba, Japan⁶

Received 23 March 2004/ Returned for modification 1 June 2004/ Accepted 5 October 2004

Understanding the protective mechanism in the liver induced by recombinant vaccines against the pre-erythrocytic stages of malaria is important for vaccine development. Most studies in mice have focused on splenic and peripheral blood T cells and identified gamma interferon (IFN-)-producing CD8⁺ T cells as correlates of protection, which can be induced by prime-boost vaccination with recombinant poxviruses. Invariant natural killer T (V14iNKT) cells can also protect against liver stage malaria, when activated, and are abundant in the liver. Since poxviruses have nonspecific immunomodulating effects, which are incompletely understood, we investigated whether recombinant poxviruses affect the protective properties of hepatic V14iNKT cells and thus vaccine efficacy. We show that intradermal vaccination with recombinant poxviruses activated V14iNKT cells and NK cells in the livers of BALB/c mice while inducing IFN-- and tumor necrosis factor alpha (TNF-)-producing pre-erythrocytic stage antigen-specific CD8⁺ T cells. Greater numbers of hepatic V14iNKT cells secreted interleukin-4 than IFN-. Vaccinated V14iNKT-cell-deficient mice had lower, but still protective levels of hepatic and splenic IFN-⁺ and TNF-⁺ CD8⁺ T cells and better protection rates later after challenge with Plasmodium berghei sporozoites. Therefore, vaccine-activated hepatic V14iNKT cells help in generating specific T cells but are not required for protection induced by recombinant poxviruses. Furthermore, double-positive INF-⁺/TNF-⁺ CD8⁺ T cells were enriched in protected livers, suggesting that cells expressing both of these cytokines may be most relevant for protection.

Editor: S. H. E. Kaufmann

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