An MHC Class II Restriction Bias in CD4 T Cell Responses toward I-A Is Altered to I-E in DM-Deficient Mice

• Published in: The Journal of immunology (1950) 2008-02, Vol.180 (3), p.1619-1633
• Main Authors: Menges, Paula R, Jenks, Scott A, Bikoff, Elizabeth K, Friedmann, David R, Knowlden, Zackery A. G, Sant, Andrea J
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; CD4-Positive T-Lymphocytes - immunology; Cytokines - metabolism; Escherichia coli Proteins - immunology; H-2 Antigens - genetics; H-2 Antigens - immunology; Haplotypes; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - immunology; HLA-D Antigens - genetics; Immunodominant Epitopes - immunology; Immunoglobulin Isotypes - genetics; Immunoglobulin Isotypes - immunology; Mice; Mice, Mutant Strains; Molecular Sequence Data; Peptides - chemistry; Peptides - immunology; Periplasmic Binding Proteins - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.180.3.1619

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.