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* Program in Immunology,
Department of Pediatrics,
Department of Chemistry,
Department of Molecular and Cellular Physiology, Structural Biology, and Howard Hughes Medical Institute,
¶ Division of Biostatistics, Department of Health Research and Policy, Stanford University, Stanford, CA 94305;
|| Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
# Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104
Several MHC class II alleles linked with autoimmune diseases form unusually low stability complexes with CLIP, leading us to hypothesize that this is an important feature contributing to autoimmune pathogenesis. To investigate cellular consequences of altering class II/CLIP affinity, we evaluated invariant chain (Ii) mutants with varying CLIP affinity for a mouse class II allele, I-Ed, which has low affinity for wild-type CLIP and is associated with a mouse model of spontaneous, autoimmune joint inflammation. Increasing CLIP affinity for I-Ed resulted in increased cell surface and total cellular abundance and half-life of I-Ed. This reveals a post-endoplasmic reticulum chaperoning capacity of Ii via its CLIP peptides. Quantitative effects on I-Ed were less pronounced in DM-expressing cells, suggesting complementary chaperoning effects mediated by Ii and DM, and implying that the impact of allelic variation in CLIP affinity on immune responses will be highest in cells with limited DM activity. Differences in the ability of cell lines expressing wild-type or high-CLIP-affinity mutant Ii to present Ag to T cells suggest a model in which increased CLIP affinity for class II serves to restrict peptide loading to DM-containing compartments, ensuring proper editing of antigenic peptides.
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1 This work was supported by funds from the National Institutes of Health (to E.D.M., C.H.R., K.C.G.), the National Science Foundation (to C.H.R.), the Arthritis Foundation (to E.D.M.), an Immunology Training Grant (to A.J.B.), the Howard Hughes Medical Institute (to T.L.W.C., K.C.G.), and the Lucille Packard Foundation for Children’s Health (to T.H.H.).
2 Current address: Arbor Vita Corporation, Sunnyvale, CA 94085.
3 Current address: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143.
4 Current address: Sidney Sussex College and Department of Medicine, Cambridge University, Cambridge, U.K.
5 Address correspondence and reprint requests to Dr. Elizabeth D. Mellins, Department of Pediatrics, Stanford University School of Medicine, 269 Campus Drive, CCSR 2115c, Stanford, CA 94305. E-mail address: mellins{at}stanford.edu
6 Abbreviations used in this paper: DC, dendritic cell; RA, rheumatoid arthritis; Ii, invariant chain; ER, endoplasmic reticulum; HEL, hen egg white lysozyme; MFI, mean fluorescence intensity; wt, wild type; GEE, generalized estimating equation; co-IP, coimmunoprecipitation; CHX, cycloheximide.
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