An MHC class II restriction bias in CD4 T cell responses toward I-A is altered to I-E in DM-deficient mice.
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.
Menges
Paula R
PR
David H. Smith Center for Vaccine Biology and Immunology, AaB Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA.
Jenks
Scott A
SA
Bikoff
Elizabeth K
EK
Friedmann
David R
DR
Knowlden
Zackery A G
ZA
Sant
Andrea J
AJ
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D006681:HLA-D Antigens / Q000235:genetics*; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D033902:Periplasmic Binding Proteins / Q000276:immunology
D016207:Cytokines; D029968:Escherichia coli Proteins; D006183:H-2 Antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D007132:Immunoglobulin Isotypes; C461619:MalE protein, E coli; D010455:Peptides; D033902:Periplasmic Binding Proteins