Recognition of major histocompatibility complex (MHC) class II/peptide complexes by the T-cell receptor is a crucial step in the activation of CD4+ T cells. Peptides for presentation on class II molecules are generated by proteolytic cleavage of extracellular proteins in the acidic environment of endosomes and lysosomes in antigen-presenting cells (APC). Reporting in Science, Maric and colleagues describe the role of a component of the processing pathway called γ-interferon-inducible lysosomal thiol reductase, GILT (also known as Ifi30), which catalyses the reduction of disulphide bonds and enhances protease access to the antigen.

In this study, Maric and colleagues cloned mouse GILT and generated a knockout mouse to investigate the role of GILT in antigen processing. Hen egg lysozyme (HEL), which contains four disulphide bonds, was used as a model antigen. The T-cell proliferative response of GILT-deficient mice that were immunized with HEL was about one-tenth that of wild-type littermates. In in vitro assays, HEL epitope-specific T cells were used to detect the presence of four specific HEL peptides presented on MHC class II molecules. Interestingly, the results were not quite as clear cut as might be expected. Whereas the response to one of the cysteine-containing epitopes was eliminated, two others were efficiently presented in the absence of GILT, indicating that proteases can access these epitopes in the absence of protein unfolding. By contrast, a cysteine-negative epitope was poorly presented in GILT-deficient mice, indicating that efficient presentation of this epitope requires the reduction of disulphide bonds outside the epitope.

So, this study shows that proteases alone are insufficient to generate the full complement of peptides from a specific antigen, and that GILT improves protease accessibility to antigen in the MHC class II processing pathway.