Inhibition by brefeldin A of presentation of exogenous protein antigens to MHC class II-restricted T cells

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Abstract
PEPTIDES bound to class I or class II major histocompatibility complex (MHC)-encoded molecules are ligands for the antigen-specific T-cell receptor of T-cells carrying the CD8 and CD4 antigens, respectively1. MHC class I-restricted T cells generally recognize peptides derived from processing of endogenously synthesized cellular antigens, whereas class II-restricted T cells usually recognize peptides derived from exogenous antigens entering antigen presenting cells. Accordingly, two separate pathways of antigen processing and presentation have been proposed2,3. The fungal metabolite brefeldin A (BFA)4, an inhibitor of protein transport from the endoplasmic reticulum5–7, inhibits presentation of endogenous antigens for MHC-restricted T-cell recognition8. The selectivity of BFA activity has been inferred to reflect presentation of a given antigen processed through the cytosolic or the endocytic route9,10. Here we show that BFA also greatly inhibits the presentation of exogenous protein antigens by MHC class II molecules to T cells, indicating a broader effect of this drug on antigen presentation and an additional similarity between the two processing pathways. As cycloheximide, a protein synthesis inhibitor, also inhibits presentation of protein antigens to class II-restricted T cells, the data indicate that peptides generated by processing of exogenous proteins bind to newly synthesized class II molecules for presentation to T cells.