Evaluation of Immunological Paradigms in a Virus Model: Are Dendritic Cells Critical for Antiviral Immunity and Viral Clearance?

• Published in: Journal of Immunology 2006-07, Vol.177 (1), p.492-500
• Main Authors: Ciavarra, Richard P, Stephens, Amber, Nagy, Sandra, Sekellick, Margaret, Steel, Christina
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; Cell Proliferation; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - virology; Diphtheria Toxin - administration & dosage; Encephalitis, Viral - genetics; Encephalitis, Viral - immunology; Encephalitis, Viral - virology; Female; Immunosuppressive Agents - administration & dosage; Interferon Type I - antagonists & inhibitors; Interferon Type I - biosynthesis; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Resting Phase, Cell Cycle - genetics; Resting Phase, Cell Cycle - immunology; Rhabdoviridae Infections - genetics; Rhabdoviridae Infections - immunology; Rhabdoviridae Infections - therapy; Rhabdoviridae Infections - virology; Spleen - cytology; Spleen - immunology; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - virology; Vesicular stomatitis Indiana virus - growth & development; Vesicular stomatitis Indiana virus - immunology; Vesicular stomatitis virus; Viral Load
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.177.1.492

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.