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Extraction of Tissue Antigens for Functional Assays
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Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register

Brian D Stadinski1, Li Zhang, Frances Crawford

  • 1Integrated Department of Immunology, University of Colorado and National Jewish Health, Denver, CO 80206, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 11, 2010
PubMed

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.

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