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Infection and Immunity, June 2008, p. 2603-2611, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01718-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Both CD4⁺ and CD8⁺ T Cells Respond to Antigens Fused to Anthrax Lethal Toxin

Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115

Received 21 December 2007/ Returned for modification 21 February 2008/ Accepted 10 March 2008

The lethal toxin produced by Bacillus anthracis is a bipartite toxin in which the first protein, protective antigen (PA), transports the second protein, lethal factor, across the host cell membrane. We have previously shown that CD8⁺ T-cell epitopes fused to a nontoxic derivative of lethal factor (LFn) are delivered into the host cell cytosol in a PA-dependent manner. Delivery of these antigens targets them to the intracellular major histocompatibility complex (MHC) class I processing and presentation pathway and leads to the stimulation of antigen-specific CD8⁺ T cells in vivo. In this report, we describe the generation and characterization of LFn fusion proteins that include not only a CD8⁺ T-cell epitope but also a CD4⁺ T-cell epitope. We first show that these fusion proteins induce antigen-specific CD4⁺ T-cell responses following incubation with dendritic cells in vitro or injection into mice. Stimulation of CD4⁺ T cells by LFn fusion proteins does not require PA but is enhanced by PA in vitro. We also show that a single LFn fusion protein and PA can deliver antigen to both the MHC class II and the MHC class I pathways, resulting in the simultaneous induction of antigen-specific CD4⁺ T cells and antigen-specific CD8⁺ T cells in the same mouse. These results suggest that this toxin delivery system is capable of stimulating protective immune responses where effective immunization requires stimulation of both classes of T cells.

Published ahead of print on 17 March 2008.

Editor: V. J. DiRita