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An MHC Class II Restriction Bias in CD4 T Cell Responses toward I-A Is Altered to I-E in DM-Deficient Mice¹

Paula R. Menges^*, Scott A. Jenks^*, Elizabeth K. Bikoff, David R. Friedmann^*, Zackery A. G. Knowlden^* and Andrea J. Sant^2,*

^* 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; and University of Oxford, Wellcome Trust Center for Human Genetics, Oxford, United Kingdom

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 AI51542, R21 AI059898 (to A.J.S.), AII19047 (to E.K.B.), training Grants T32 AI 007285 (to P.R.M.), and T32 HL66988 (to S.A.J.), and by the Wellcome Trust.

² Address correspondence and reprint requests to Dr. Andrea J. Sant, University of Rochester, 601 Elmwood Avenue, Box 609, Kornberg Medical Research Building, Room 396-45, Rochester, NY 14642. E-mail address: andrea_sant{at}urmc.rochester.edu

³ Abbreviations used in this paper: DM, HLA-DM or H-2DM; CLIP, class II-associated invariant chain peptide; WT, wild type; LACK, Leishmania homologue of activated receptor for c-kinase; MalE, maltose-binding protein of Escherichia coli; HEL, hen egg lysozyme.

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				K. A. Richards, F. A. Chaves, and A. J. Sant Infection of HLA-DR1 Transgenic Mice with a Human Isolate of Influenza A Virus (H1N1) Primes a Diverse CD4 T-Cell Repertoire That Includes CD4 T Cells with Heterosubtypic Cross-Reactivity to Avian (H5N1) Influenza Virus J. Virol., July 1, 2009; 83(13): 6566 - 6577. [Abstract] [Full Text] [PDF]