title: Evaluation of immunological paradigms in a virus model: are dendritic cells critical for antiviral immunity and viral clearance?
abstract: We have examined the role of dendritic cells (DCs) in the antiviral immune response and viral clearance using a transgenic mouse model (CD11c-diphtheria toxin (DT) receptor GFP) that allows for their conditional ablation in vivo. DT administration systemically ablated conventional and IFN-producing plasmacytoid DCs (pDCs) in transgenic, but not nontransgenic littermates, without elimination of splenic macrophages. Unexpectedly, early (12 and 48 h postinfection) viral clearance of vesicular stomatitis virus was normal in DC-depleted mice despite markedly reduced serum titers of type I IFN. DC-depleted mice remained virus-free with the exception of a subset (approximately 30%) that developed overwhelming and fatal brain infections 6 days postinfection. However, DT treatment profoundly inhibited clonal expansion of naive CD8+ vesicular stomatitis virus-specific T cells without altering the primary Th1 and Th2 cytokine response. Optimal clonal expansion required pDCs because selective elimination of these cells in vivo with a depleting Ab also suppressed expansion of tetramer+ cells, although Th1/Th2 cytokine production remained unaltered. Collectively, these data indicate that conventional DCs and to a lesser extent pDCs are critical for proliferation of naive antiviral T cells. However, other components of the primary adaptive immune response (Th1/Th2 cytokines) are essentially normal in the absence of DCs, which may account for the efficient viral clearance seen in DC-depleted mice. Thus, sufficient redundancy exists in the immune system to sustain efficient viral clearance despite loss of an APC considered essential for induction of a primary antiviral immune response.
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, 700 Olney Road, Norfolk, VA 23501, USA. ciavarrp@evms.edu
authors.forename: Richard P
authors.initials: RP
authors.lastname: Ciavarra
authors.forename: Amber
authors.initials: A
authors.lastname: Stephens
authors.forename: Sandra
authors.initials: S
authors.lastname: Nagy
authors.forename: Margaret
authors.initials: M
authors.lastname: Sekellick
authors.forename: Christina
authors.initials: C
authors.lastname: Steel
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D004167:Diphtheria Toxin / Q000008:administration & dosage; D018792:Encephalitis, Viral / Q000235:genetics / Q000276:immunology / Q000821:virology; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D018353:Rhabdoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000628:therapy / Q000821:virology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000254:growth & development / Q000276:immunology*; D019562:Viral Load
chemical_list: D004167:Diphtheria Toxin; D007166:Immunosuppressive Agents; D007370:Interferon Type I