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The ABCs of antigen presentation : defining antigen processing pathways

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Title: The ABCs of antigen presentation : defining antigen processing pathways
Author: Johnson, Laura Alexandra
Degree Doctor of Philosophy - PhD
Program Zoology
Copyright Date: 2004
Abstract: The ATP-binding cassette (ABC) transporter TAP (ABCB2/3) is an integral component of the endogenous antigen processing pathway. Without TAP, antigenic peptides cannot enter the ER to bind to class I MHC molecules en route to the cell surface, and as a result, no cellmediated immune response can occur. All normal cells can present endogenous antigens, but exogenous antigen presentation is conducted solely by professional antigen presenting cells (APCs). The precise mechanism of intracellular transport of these exogenous antigens remains unknown. As TAP plays an integral role in endogenous peptide transport, it is conceivable that other ABC transporters play a similar role in exogenous antigen processing. Using RT-PCR, gene expression of all 46 known murine ABC transporters was assayed in APCs and non-APCs in response to various stimulatory cytokines and exogenous antigens. A pattern emerged, whereby APCs induced many specific ABC genes compared to non-APCs, and activated dendritic cells (DCs) expressed the highest number. Incorporating information based on the evolutionary phylogeny of sequence similarity to known antigen transporters, 18 candidate antigen presenting genes were identified. The ABCB9 transporter gene shared the highest sequence homology to the TAP genes, was differentially expressed in activated DCs, and localized to endosome and lysosomal compartments. An ABCB9[sup -/-] mouse was made and characterized for an immunological phenotype. While no defect in live viral immune response was observed, a defective T-cell response to cross-presented exogenous antigens such as ovalbumin and heat-inactivated Sendai virus was discovered, but not to MHC class-II restricted antigens. This defect was traced back to an inability of ABCB9[sup -/-] DCs to present these antigens on the cell surface, and was consistent with a lack of antigen transport between the endo/lysosome and the cytoplasm, as introduction of endogenous antigen corrected the defect. The contribution of the ABCB9 gene to cancer immunology was then evaluated, and it was found that upon challenge with live tumour cells, pre-immunized ABCB9[sup -/-] mice were no more susceptible than wild-type mice. Thus, exogenous antigen presentation is not the primary method by which a cellular anti-tumour response is primed in-vivo.
URI: http://hdl.handle.net/2429/17320
Series/Report no. UBC Retrospective Theses Digitization Project [http://www.library.ubc.ca/archives/retro_theses/]

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