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Modulation of the MHC class I antigen processing and presentation pathway

University of British Columbia

Antigen processing and presentation are central to the complex immune response elicited upon infections by pathogens. They result in the generation of peptides that can be presented to T cells and elicit specific immune responses. Two distinct pathways process and present foreign antigens and are respectively mediated through MHC class I and class II molecules. Although much has been learned about these pathways in recent years, their details remain to be resolved. The present study further examines the MHC class I pathway. To this end, two distinct approaches were undertaken. First, we examined the ability of Adenovirus type 2 to block this pathway. Thus far, this phenotype had solely been attributed to the E3/19K viral protein. Since past characterizations were unexpectedly done in the presence of other viral proteins, including E3/6.7K, we sought to determine the role of E3/6.7K on this phenotype and to further characterize its properties. Using a bank of viral deletion mutants, lacking either E3/6.7K or E3/19K, we found a specific interaction between E3/6.7K and E3/19K. Despite this interaction, E3/6.7K did not affect MHC class I surface expression or phosphorylation. However, we report the novel finding that at least one additional viral protein was necessary for the optimal down regulation of MHC class I surface expression by the virus. Unexpectedly, the detection of disulfide bonds in E3/6.7K suggested that it likely had a peculiar orientation in the ER membrane. In the second approach, we examined the ability of a mutant cell line, gro29, deficient for HSV-1 viral egress, to process and present peptides to T cells. The results indicated that gro29 had a slight, but likely inconsequential, deficiency in the processing of molecules through its secretory pathway and had a normal complement of proteins at its surface. Surprisingly, this mutant was deficient for the presentation of HSV-1 peptides, but normally processed and presented allogeneic and Influenza peptides. Most important, this dichotomy indicated the existence of distinct MHC class I processing and presentation pathways. Overall the data revealed a complex interaction between Adenovirus type 2 and the MHC class I processing and presentation pathway. They also underlined the usefulness of the gro29 variant cell line as mutant antigen processing and presentation cells.

Thesis/Dissertation

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2009-04-22

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http://hdl.handle.net/2429/7490

Microbiology and Immunology

University of British Columbia

UBCV

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