Cellular Biology and Viral Immunology Sections

Lab members: Sameh Basta, Ph.D.; Peter Berglund, Ph.D.; Diana Finzi, Ph.D.; Felicita Hornung, Ph.D.; Tara Palmore, M.D.; Nathalie Pardigon, Ph.D.; Michael Princiotta, Ph.D.; Shubing Qian, Ph.D.; Ulrich Schubert, Ph.D.; David Tscharke, Ph.D. Shanicka Williams

Research Staff: James Gibbs, Ph.D.; Daniela Malide, M.D., Ph.D.; Deborah Tokarchick, MS

Description of Research Program:

Class I molecules of the major histocompatibility complex (MHC) function to display oligopeptides derived from intracellular proteins to T cells bearing CD8 molecules (T_CD8+). T_CD8+ play a critical role in eradicating intracellular pathogens (particularly viruses) and tumors. On the negative side of the ledger, T_CD8+ contribute to autoimmunity and rejection of transplanted tissues. Due to the importance of T_CD8+ in health and disease, considerable effort has gone into delineating the physical nature of the antigen-class I complex and understanding how class I binding peptides are generated and assembled with class I molecules ("antigen processing"). There is now Ångström-level resolution of class I-peptide complexes and a broad outline of the principal class I antigen processing pathways. Many important questions regarding the class I antigen processing remain, particularly those concerned with how class I binding peptides are generated. Armed with knowledge regarding antigen processing and presentation gleaned from in vitro systems combined with novel reagents that enable detection of specific class I-peptide complexes and T_CD8+ specific for these complexes, it is now possible to tackle important questions regarding the in vivo generation of anti-viral T_CD8+ responses. We are committed to apply recent advances in light microscopy to visualize in real time the interactions anti-viral T_CD8+ with professional- and non-professional antigen presenting cells in vivo.

The broad objectives of the Cellular Biology and Viral Immunology Sections are to:

1. Discover and define basic cellular processes involved in the generation of MHC class I peptide ligands.
2. Gain a fundamental understanding of the underlying in vivo cellular events that lead to presentation of viral antigens to T_CD8+ and the regulation of anti-viral T_CD8+ responses.

Keywords: Antigen presentation/processing, Viral immunity, T lymphocytes, MHC class I molecules, Ubiquitin/Proteasome

Some Recent Publications:

1. Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR (2000). Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770-774.
2. Schubert U, Ott D, Chertova EN, Welker R, Tessmer U, Princiotta M, Bennink JR, Krausslich HG, Yewdell JW (2000). Proteasome inhibition interferes with Gag polypeptide processing, release and maturation of human immunodeficiency viruses. Proc. Natl. Acad. Sci. 97:13057-13062.
3. Chen W, Norbury CC, Cho Y, Yewdell JW, Bennink JR (2001). Immunoproteasomes shape immunodominance hierarchies of anti-viral CD8+ T cell at the levels of T cell repertoire and presentation of viral antigens J. Exp. Med. 193:1319-1326.
4. Norbury CC, Princiotta MF, Bacik I, Brutkiewicz RR, Wood P, Elliot T, Bennink JR, Yewdell JW (2001) Multiple antigen-specific processing pathways for activating naïve CD8+ T-cells in vivo. J. Immunol. 166: 4355-4362.
5. Chen W, Calvo PA, Malide D, Gibbs J, Bacik I, Basta S, O'Neill R, Schickli J, Palese P, Henklein P, Bennink JR, Yewdell JW (2001). A novel influenza A virus mitochondrial protein that induces cell death. Nature Med. 7:1306-1312.
6. Norbury CC, Malide D, Gibbs J, Bennink JR, Yewdell JW. (2002). Visualization of virus-specific CD8+ T-cells by infected dendritic cells in vivo. Nature Immunology. 3: 265-271.
7. Basta, S, Chen, W, Bennink, JR, Yewdell, JW (2002). Inhibitory effects of cytomegalovirus proteins US2 and US11 point to contributions from direct priming and cross priming in induction of vaccinia virus specific CD8+ T cells. J. Immunol., 168:5403-5408.
8. Qian S, Ott DE, Schubert U, Bennink JR, Yewdell JW (2002). Fusion proteins with COOH-terminal ubiquitin are stable and maintain dual functionality in vivo. J. Biol. Chem., in press.
9. Gibbs JS, Malide D, Hornung F, Bennink JR, Yewdell JY. The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function submitted J. Virology
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