IFN-gamma affects both the stability and the intracellular transport of class I MHC complexes

In accordance with the key role of major histocompatibility complex (MHC) class I molecules in the adaptive immune response against viruses, their expression can be enhanced by the potent cytokine interferon-gamma (IFN-gamma), which upregulates the expression of multiple components in the pathway of class I-restricted antigen presentation. In this study, we analyzed the effect of IFN-gamma treatment on class I formation, peptide editing, trafficking, and cell surface expression. We show that IFN-gamma treatment promotes significantly the assembly and cell surface expression of stable class I complexes. Yet the existence of large intracellular pools of both free class I heavy chains and suboptimal class I complexes indicates that the optimal peptide supply limits cell surface expression levels of class I complexes. Unexpectedly, we found that IFN-gamma appears generally to slow the maturation rates of both class I complexes and transferrin receptors. Apparently, IFN-gamma causes prolonged retention of molecules in the endoplasmic reticulum (ER) because it regulates the expression of ER-residing proteins that participate in protein maturation. Consequently, it induces more rigorous ER quality control. The significance of these effects of IFN-gamma for in vivo immune responses is discussed.