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A CD8⁺ T Cell Heptaepitope Minigene Vaccine Induces Protective Immunity against Chlamydia pneumoniae¹

Irina Pinchuk^*,, Barry C. Starcher, Brian Livingston, Amy Tvninnereim^*,, Shiping Wu^*, Ettore Appella^||, John Sidney^¶, Alessandro Sette^¶ and Benjamin Wizel^2,*,

^* Center for Pulmonary and Infectious Disease Control, Departments of Microbiology and Immunology and Biochemistry, University of Texas Health Center, Tyler, TX 75708; Epimmune and ^¶ La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; and ^|| National Cancer Institute, Bethesda, MD 20892

An intact T cell compartment and IFN- signaling are required for protective immunity against Chlamydia. In the mouse model of Chlamydia pneumoniae (Cpn) infection, this immunity is critically dependent on CD8⁺ T cells. Recently we reported that Cpn-infected mice generate an MHC class I-restricted CD8⁺ Tc1 response against various Cpn Ags, and that CD8⁺ CTL to multiple epitopes inhibit Cpn growth in vitro. Here, we engineered a DNA minigene encoding seven H-2^b-restricted Cpn CTL epitopes, the universal pan-DR epitope Th epitope, and an endoplasmic reticulum-translocating signal sequence. Immunization of C57BL/6 mice with this construct primed IFN--producing CD8⁺ CTL against all seven CTL epitopes. CD8⁺ T cell lines generated to minigene-encoded CTL epitopes secreted IFN- and TNF- and exhibited CTL activity upon recognition of Cpn-infected macrophages. Following intranasal challenge with Cpn, a 3.6 log reduction in mean lung bacterial numbers compared with control animals was obtained. Using a 20-fold increase in the Cpn challenging dose, minigene-vaccinated mice had a 60-fold reduction in lung bacterial loads, compared with controls. Immunization and challenge studies with ₂-microglobulin^–/– mice indicated that the reduction of lung Cpn burdens was mediated by the MHC class I-dependent CD8⁺ T cells to minigene-included Cpn CTL epitopes, rather than by pan-DR epitope-specific CD4⁺ T cells. This constitutes the first demonstration of significant protection achieved by immunization with a CD8⁺ T cell epitope-based DNA construct in a bacterial system and provides the basis for the optimal design of multicomponent anti-Cpn vaccines for humans.

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