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International Immunology Advance Access originally published online on May 21, 2009
International Immunology 2009 21(6):705-713; doi:10.1093/intimm/dxp039
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© The Author 2009. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press and The Japanese Society for Immunology are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Prediction of HLA-DQ8 β cell peptidome using a computational program and its relationship to autoreactive T cells

Kuan Y. Chang1,2 and Emil R. Unanue1

1 Division of Immunology, Department of Pathology and Immunology
2 Computational Biology Program, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St Louis, MO 63110, USA

Correspondence to: E. R. Unanue; E-mail: unanue{at}pathbox.wustl.edu

The goal was to identify HLA-DQ8-bound β cell epitopes important in the T cell response in autoimmune diabetes. We first identified HLA-DQ8 (DQA1*0301/DQB1*0302) β cell epitopes using a computational approach and then related their identification to CD4 T cell responses. The computational program (TEA-DQ8) was adapted from one previously developed for identifying peptides bound to the I-Ag7 molecule and based on a library of naturally processed peptides bound to HLA-DQ8 molecules of antigen-presenting cells. We then examined experimentally the response of NOD.DQ8 mice immunized with peptides derived from the Zinc transporter 8 protein. Log-of-odds scores on peptides were experimentally validated as an indicator of peptide binding to HLA-DQ8 molecules. We also examined previously published data on diabetic autoantigens, including glutamic acid decarboxylase-65, insulin and insulinoma-associated antigen-2, all tested in NOD.DQ8 transgenic mice. In all examples, many peptides identified with a favorable binding motif generated an autoimmune T cell response, but importantly many did not. Moreover, some peptides with weak-binding motifs were immunogenic. These results indicate the benefits and limitations in predicting autoimmune T cell responses strictly from MHC-binding data. TEA-DQ8 performed significantly better than other prediction programs

Keywords: HLA-DQ8, MHC class II molecules, T cell epitope prediction, type I diabetes mellitus

Transmitting editor: M. Feldmann

Received 7 October 2008, accepted 6 April 2009.


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