| Presentation and CD4+ T cell responses to antigen in the context of MHC class II molecules require processing of native proteins into short peptide fragments. Within this pathway, GILT (G&barbelow;amma-interferon I&barbelow;nducible L&barbelow;ysosomal T&barbelow;hiol Reductase), functions to catalyze thiol bond reduction, thus unfolding native protein antigens and facilitating further processing via cellular proteases. In contrast with professional antigen presenting cells such as B cells, class II positive human melanomas expressed relatively little to no GILT protein or mRNA. Tumor cell GILT expression was partially restored with IFN-gamma treatment but unlike other genes required for class II antigen presentation, GILT was not regulated by CIITA. Rather, studies revealed that two members of the Stat family of transcription factors, Stat1 and Stat3, play a direct role in IFN-gamma inducible GILT expression in human melanomas. These results define a molecular mechanism for the uncoupled regulation of MHC class II genes and the processing enzyme GILT in human melanomas. |
