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A Mutant Cell with a Novel Defect in MHC Class I Quality Control¹

Ian A. York^2,*, Ethan P. Grant^3,, A. Maria Dahl^4, and Kenneth L. Rock^*

^* Department of Pathology, University of Massachusetts Medical Center, Worcester, MA 01655; and Dana-Farber Cancer Institute, Boston, MA 02115

COS7 (African Green Monkey kidney) cells stably transfected with the mouse MHC class I allele H-2K^b were mutagenized, selected for low surface expression of endogenous MHC class I products, and subcloned. A mutant cell line, 4S8.12, expressing very low surface MHC class I (5% of parental levels) was identified. This cell line synthesized normal levels of the MHC class I H chain and ₂-microglobulin, as well as normal levels of TAP, tapasin, GRP78, calnexin, calreticulin, ERp57, and protein disulfide isomerase. Full-length OVA was processed to generate presented H-2K^b-SIINFEKL complexes with equal efficiency in wild-type and mutant cells, demonstrating that proteasomes, as well as TAP and tapasin, functioned normally. Therefore, all the known components of the MHC class I Ag presentation pathway were intact. Nevertheless, primate (human and monkey) MHC class I H chain and ₂-microglobulin failed to associate to form the normal peptide-receptive complex. In contrast, mouse H chains associated with ₂-microglobulin normally and bound peptide at least as well as in wild-type cells. The 4S8.12 cells provide strong genetic evidence for a novel component in the MHC class I pathway. This as-yet unidentified gene is important in early assembly of primate, but not mouse, MHC class I complexes.