Brefeldin A implicates egress from endoplasmic reticulum in class I restricted antigen presentation.
Most antigens must be processed intracellularly before they can be presented, in association with major histocompatibility complex (MHC) molecules at the cell surface, for recognition by the antigen-specific receptor of T cells. This processing appears to involve cleavage of protein antigens to smaller peptides. Only certain fragments of any protein can serve as T-cell epitopes and this is, at least in part, determined by the requirement that peptides be able to bind the MHC molecules. Class I restricted antigens are derived from proteins, such as viral antigens, that are synthesized within the presenting cell. Many of these antigens are cytosolic proteins and recent evidence suggests that it is in the cytosol that these proteins are processed to produce either the antigenic peptides or processed intermediates. How and where these processed cytosolic antigens cross the membrane of the vacuolar system and bind to the extracellular domain of the class I molecule is not known but one obvious site for this process is the endoplasmic reticulum (ER), because this organelle is specialized to translocate proteins across the membrane from the cytosol into the secretory system. Based on this model, we reasoned that if we could pharmacologically block the movement of proteins out of the ER, endogenous antigen presentation would cease. An agent which causes such an effect is available--the fungal antibiotic Brefeldin A (BFA). Consistent with the above hypothesis, we report that BFA completely abolishes the ability of a cell to present endogenously synthesized antigens to class I restricted cytotoxic T cells.
Nuchtern
J G
JG
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892.
Bonifacino
J S
JS
Biddison
W E
WE
Klausner
R D
RD
D000956:Antigens, Viral / Q000276:immunology*; D020126:Brefeldin A; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology*; D003600:Cytosol / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004721:Endoplasmic Reticulum; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects
D000956:Antigens, Viral; D003517:Cyclopentanes; D015395:Histocompatibility Antigens Class I; D020126:Brefeldin A