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The MHC-encoded cofactor DM catalyzes endosomal loading of peptides onto MHC class II molecules. Despite evidence from in vitro experiments that DM acts to selectively edit the repertoire of class II:peptide complexes, the consequence of DM expression in vivo, or a predictive pattern of DM activity in the specificity of CD4 T cell responses has remained unresolved. Therefore, to characterize DM function in vivo we used wild-type (WT) or DM-deficient (DM(-/-)) mice of the H-2(d) MHC haplotype and tested the hypothesis that DM promotes narrowing of the repertoire of class II:peptide complexes displayed by APC, leading to a correspondingly selective CD4 T cell response. Surprisingly, our results indicated that DM(-/-) mice do not exhibit a broadened CD4 T cell response relative to WT mice, but rather shift their immunodominance pattern to new peptides, a pattern associated with a change in class II isotype-restriction. Specifically, we found that CD4 T cell responses in WT mice were primarily restricted to the I-A class II molecule, whereas DM(-/-) mice recognize peptides in the context of I-E. The observed shift in isotype-restriction appeared to be due in part to a modification in the peripheral CD4 T cell repertoire available for peptide recognition.

Type

Journal article

Journal

J Immunol

Publication Date

01/02/2008

Volume

180

Pages

1619 - 1633

Keywords

Amino Acid Sequence, Animals, CD4-Positive T-Lymphocytes, Cytokines, Escherichia coli Proteins, H-2 Antigens, HLA-D Antigens, Haplotypes, Histocompatibility Antigens Class II, Immunodominant Epitopes, Immunoglobulin Isotypes, Mice, Mice, Mutant Strains, Molecular Sequence Data, Peptides, Periplasmic Binding Proteins