T cell recognition of the dominant I-A(k)-restricted hen egg lysozyme epitope: critical role for asparagine deamidation.
Type-B T cells raised against the immunodominant peptide in hen egg lysozyme (HEL(48-62)) do not respond to whole lysozyme, and this has been thought to indicate that peptide can bind to l-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.
McAdam
S N
SN
Institute of Immunology, University of Oslo, Rikshospitalet, Oslo N-0027, Norway. stephen.mcadam@labmed.uio.no
Fleckenstein
B
B
Rasmussen
I B
IB
Schmid
D G
DG
Sandlie
I
I
Bogen
B
B
Viner
N J
NJ
Sollid
L M
LM
D000595:Amino Acid Sequence; D000818:Animals; D001216:Asparagine / Q000378:metabolism*; D015551:Autoimmunity; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D009113:Muramidase / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D001216:Asparagine; C421864:hen egg lysozyme; D009113:Muramidase