Brazil, Melanie Ida; (1997) Presentation of intracellular antigen with MHC class II molecules. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Antigen presenting cells internalize exogenous protein and degrade it in the endocytic pathway into peptides which bind to MHC class II molecules. This complex is displayed on the cell surface where it can activate class II-restricted T cells. This work compares the ability of different antigen presenting cells, expressing endogenous C5 (fifth component of mouse complement), to present their biosynthesized C5 to MHC class Il-restricted C5-specific T cells. B cells and fibroblasts were able to present several epitopes of their endogenous C5 with class II molecules, whereas macrophages were not. However, macrophages were able to present endogenous C5 if treated with low doses of the lysosomotropic agent, ammonium chloride. All transfectants were able to present C5 from an exogenous source. The level of endogenous presentation of the B cell transfectants correlated with the relative amount of C5 expression. The presentation was ammonium chloride, chloroquine, leupeptin and pepstatin A sensitive, but aprotinin and E64 insensitive; indicating that C5 processing and presentation requires acidic compartments as well as aspartic acid and serine proteases. In the presence of an inhibitor of autophagy - a process whereby ER derived vesicles fuse with lysosomes - presentation of endogenous C5 was abrogated, whilst that of exogenous C5 was unaffected. This suggests that an autophagic mechanism is responsible for shuttling C5 into the endocytic pathway. Taken together, this study suggests that C5 destroyed in macrophage lysosomes, and that proteolytic activity in lysosomes of macrophages is greater than that in B cells and fibroblasts. Alternatively, it suggests that there may inherent differences in presentation trafficking pathways between antigen presenting cell types.

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