Intracellular processing events leading to MHC class-II mediated presentation of a cytoplasmic antigen

The MHC class II pathway typically presents exogenous antigens to CD4 + T cells in order to stimulate an immune response. However, endogenous antigens can also be presented in a MHC class II-restricted manner. While the events leading to presentation of exogenous antigens are fairly well understood, the events surrounding processing of endogenous antigens are still unclear. The model endogenous antigen used in these studies, glutamate decarboxylase (GAD), is an important autoantigen in the development of insulin dependent diabetes mellitus.; Before binding to MHC class II molecules, endogenous antigens must be processed within the cytoplasm. A novel role for two constitutive heat shock proteins, HSC70 and HSP90, in the processing of GAD is shown here. Both proteins were observed to bind to GAD, and each was required for efficient presentation of the endogenous GAD protein. HSC70 and HSP90 also provide a potential link to the two cytoplasmic proteases, calpain and the proteasome, which are key in generating smaller GAD fragments. It was observed that the GAD protein is ubiquitintated, and that inhibition of the proteasome promotes GAD stability. A calpain isoform which requires the calpain small regulatory subunit was also found to be key to endogenous GAD presentation.; Once GAD has been cleaved into peptide fragments, these fragments must enter the endocytic pathway and transit to the MIIC to be loaded onto waiting class II molecules. It is in this compartment that the HLA-DM molecule is able to remove the low affinity GAD_273–285 peptide and thus prevent its presentation. DM mediated editing occurs regardless of the antigen source, but it does depend on the level of DM within the cell.; These studies further define the key players involved in the complicated pathway leading to MHC class II-restricted presentation of endogenous antigens. Such knowledge is valuable not only for basic understanding of this pathway, but also for a clearer understanding of both autoimmune and anti-tumor responses mediated by the immune system.