December 2007

Document Type


Degree Name



Dept. of Molecular Microbiology and Immunology


Oregon Health & Science University


Mycobacterium tuberculosis (Mtb) resides in a phagosome that resists maturation. While this compartment is accessible to the Class II processing pathway, the mechanisms by which Mtb antigens are processed and presented on Class I molecules is poorly understood. In this dissertation, I present findings which characterize the pathway by which ten Mtb epitopes, presented by both classical and nonclassical Class I molecules are processed in dendritic cells. We find that Mtb antigens access the cytosol by retrotranslocation from the phagosome. Here, Mtb proteins are degraded by the proteasome or a potentially novel cytosolic protease. Peptides derived from cytosolic proteolysis are transported by TAP, and nine of ten epitopes require ER-golgi transport to the cell surface. In contrast to these epitopes, nonclassical antigen presentation of HLA-E associated antigen does not require ER-golgi transport or new protein synthesis, suggesting that HLA-E loading does not occur in the ER. Instead, HLA-E loading occurs in the phagosome, with the aid of phagosome-localized members of the Class I peptide loading complex. Furthermore, Class I presentation of Mtb antigens does not rely on the Mtb virulence locus, Region of Difference 1, which has been hypothesized to create a pore in the phagosomal membrane. Together these data demonstrate that the cytosolic pathway of cross-presentation is the dominant pathway for Mtb antigen presentation and that the Mtb phagosome is able to participate in presentation of Class I antigens. Also, presentation by HLA-E follows a similar but distinct processing pathway compared to classical Class I molecules. Finally, an undefined cytosolic protease may be involved in generation of class I epitopes.




School of Medicine



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