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Plasmid DNA Encoding CCR7 Ligands Compensate for Dysfunctional CD8⁺ T Cell Responses by Effects on Dendritic Cells¹

Laboratory of Viral Immunology, Department of Microbiology, University of Tennessee, Knoxville, TN 37996

Lymphotoxin -deficient (LT^-/-) mice, which lack lymph nodes and possess a disorganized spleen, develop dysfunctional CD8⁺ T cells upon HSV infection and readily succumb to herpes encephalitis. Such mice do develop apparently normal peptide-specific CD8⁺ T cell responses, as measured by MHC class I tetramer staining, but the majority of cells fail to become cytotoxic or express peptide-induced IFN- production. In the present study, we demonstrate that functional defects of CD8⁺ T cells in LT^-/- mice can be largely rectified by the administration of plasmid DNA encoding CCR7 ligands before HSV infection. Treated mutant mice developed increased peptide-specific cytotoxic responses, enhanced numbers of CD8⁺ T cells capable of producing IFN-, as well as improved resistance to HSV challenge. The corrective effect of chemokine treatment appeared to result from improved dendritic cell-mediated Ag presentation. Thus, a major consequence of the treatment was an increase in splenic dendritic cell number in CCR7 ligand-treated LT^-/- mice with such splenocyte populations showing improved APC activity in vitro. Our results document that functional defects of CD8⁺ T cells can be corrected, and indicate the value of plasmid vector encoding appropriate chemokines to achieve such immunotherapy.

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