T cell recognition of the dominant I-Ak-restricted hen egg lysozyme epitope:: Critical role for asparagine deamidation

Type-B T cells raised against the immunodominant peptide in hen egg lysozyme (HEL48-62) do not respond to whole lysozyme, and this has been thought to indicate that peptide can bind to 1-A(k) in different conformations. Here we demonstrate that such T cells recognize a deamidated form of the HEL peptide and not the native peptide. The sequence of the HEL epitope facilitates rapid and spontaneous deamidation when present as a free peptide or within a flexible domain. However, this deamidated epitope is not created within intact lysozyme, most likely because it resides in a highly structured part of the protein. These findings argue against the existence of multiple conformations of the same peptide-MHC complex and have important implications for the design of peptide-based vaccines. Furthermore, as the type-B T cells are known to selectively evade induction of tolerance when HEL is expressed as a transgene, these results suggest that recognition of posttranslationally modified self-antigen may play a role in autoimmunity.