Invariant chain alters the malignant phenotype of MHC class II⁺ tumor cells

T lymphocytes usually recognize endogenously encoded Ag in the context of MHC class I molecules, whereas exogenous Ag is usually presented by MHC class II molecules. In vitro studies in model systems suggest that presentation of endogenous Ag by class II molecules is inhibited by the association of class II with its invariant chain (Ii). In the present study we test this hypothesis in an in vivo system in which endogenously encoded tumor peptides are presented by tumor cell MHC class II molecules. In this system, transfection of syngeneic MHC class II genes (Aa^k and Ab^k) into a highly malignant, Ii negative, mouse tumor (SaI sarcoma) produces an immunogenic tumor (SaI/A^k) that is rejected by the autologous host. The class II⁺ transfectants also effectively immunize autologous A/J mice against a subsequent challenge of wild-type class II^- tumor cells. We have hypothesized that the SaI/A^k transfectants induce protective immunity because they function as APC for endogenously synthesized tumor peptides, and thereby stimulate tumor-specific Th cells, by-passing the need for professional APC. To test the role of Ii as an inhibitor of presentation of endogenous peptides, SaI/A^k tumor cells were supertransfected with Ii gene (SaI/A^k/Ii cells), and the tumorigenicity of the resulting cells determined. Nine SaI/A^k/Ii clones were tested, and their malignancy compared with that of SaI/A^k and SaI cells. Seven of the nine class II⁺/Ii⁺ tumor cells are more malignant than class II⁺/Ii^- tumor cells in autologous A/J mice. Expression of Ii therefore restores the malignant phenotype, presumably by preventing presentation of endogenously synthesized tumor peptides. Ii therefore regulates Ag presentation and can be a critical parameter for in vivo tumor immunity.