The normal function of the Ii protein is to ensure that only extracellular antigens (e.g., from virally infected or tumor cells) are presented by MHC class II molecules. It does so by blocking the antigenic peptide binding trough of MHC class II molecules at synthesis. The Ii protein is only removed in a coordinated process tightly linked to charging of class II molecules with peptides obtained from phagocytosed extracellular material (Figure 2a). When MHC class II molecules are synthesized in the absence of Ii, they are able to acquire and present antigens derived from intracellularly synthesized proteins, similar to the ‘survey’ function of MHC class I molecules that present antigens to cytotoxic T cells. In the case of tumor cells, it has been shown that they can effectively be forced to present tumor antigens when induced to express MHC class II molecules in the absence of Ii (Figure 2b). A number of studies have shown that this is sufficient to prevent tumor growth both in prevention and cure models (see references).

Another application of the Ii suppression technology is as an adjunct to DNA vaccines. In this case, the antigenic peptide encoded by the vaccine is synthesized intracellularly and will be available both for presentation by MHC class I and II molecules (i.e., when Ii expression is suppressed).

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