Date

December 2007

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Molecular Microbiology and Immunology

Institution

Oregon Health & Science University

Abstract

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.

Identifier

doi:10.6083/M45Q4T3D

School

School of Medicine

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