title: Plasmid DNA encoding CCR7 ligands compensate for dysfunctional CD8+ T cell responses by effects on dendritic cells.
abstract: Lymphotoxin alpha-deficient (LTalpha-/-) 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-gamma production. In the present study, we demonstrate that functional defects of CD8+ T cells in LTalpha-/- 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-gamma, 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 LTalpha-/- 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.
authors.affiliation: Laboratory of Viral Immunology, Department of Microbiology, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Eo
authors.forename: U
authors.initials: U
authors.lastname: Kumaraguru
authors.forename: B T
authors.initials: BT
authors.lastname: Rouse
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000235:genetics; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D020803:Encephalitis, Herpes Simplex / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008233:Lymphotoxin-alpha / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010957:Plasmids; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000819:agonists*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC; D008233:Lymphotoxin-alpha; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D007371:Interferon-gamma