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Diabetogenic T cells recognize insulin bound to IA g7 in an unexpected, weakly binding register
Brian D. Stadinski, Li Zhang, Frances Crawford, Philippa Marrack, George S. Eisenbarth and John W. Kappler
Proceedings of the National Academy of Sciences of the United States of America
Vol. 107, No. 24 (June 15, 2010), pp. 10978-10983
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/20724003
Page Count: 6
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A peptide derived from the insulin B chain contains a major epitope for diabetogenic CD4⁺ T cells in the NOD mouse model of type 1 diabetes (T1D). This peptide can fill the binding groove of the NOD MHCII molecule, IA g7 , in a number of ways or "registers." We show here that a diverse set of NOD anti-insulin T cells all recognize this peptide bound in the same register. Surprisingly, this register results in the poorest binding of peptide to IA g7 . The poor binding is due to an incompatibility between the p9 amino acid of the peptide and the unique IA g7 p9 pocket polymorphisms that are strongly associated with susceptibility to T1D. Our findings suggest that the association of autoimmunity with particular MHCII alleles may be do to poorer, rather than more favorable, binding of the critical self-epitopes, allowing T-cell escape from thymic deletion.
Proceedings of the National Academy of Sciences of the United States of America © 2010 National Academy of Sciences