When scientists think of the immune system's antigen selection procedure, oxidation/reduction is just about the last thing to come to mind. Yet the group now shows that an oxidation step by protein disulfide isomerase (PDI) helps load antigenic peptides into MHC class I molecules, which then present the antigen on the cell surface.
PDI is best known as a chaperone, but the authors found it associated with ER proteins that pull antigens into the ER from the cytosol. Its chaperone activity seems to be intact here: it binds strongly to antigens and probably protects them from the abundant ER proteases. But PDI's role goes beyond chaperone duties.
PDI also regulates a disulfide bond in the peptide-binding sites of MHC class I molecules. Only in its oxidized form, the authors find, does an MHC class I molecule accept antigenic peptides. This oxidation is performed by PDI when optimal, high-affinity antigens are abundant. In their absence, however, PDI instead reduces MHC (cells contain an equilibrium of oxidized and reduced forms of PDI). The big mystery that remains is whether and how PDI distinguishes between optimal and suboptimal peptides, particularly since each type of MHC class I molecule has its own antigen preferences.
This selective sampling is important because cells may have only about four hours to present antigens before certain virus replicate and escape. In this time, MHC molecules have to sample lots of possible antigens before finding the right one. According to Ahn, “the PDI delivery function is what might help MHC find a substrate quickly enough to mount an immune response.” In the absence of PDI's peptide-binding activity, most surface MHC class I molecules were empty, probably because they left the ER with low-affinity peptides that quickly fell off.
If the authors reduced PDI levels, virus-infected cells were unable to activate T cell responses. Cytomegalovirus brings about this defenseless state on its own by using its US3 protein to degrade PDI.