International Immunology, Vol. 11, No. 5, 835-843,
May 1999
© 1999 Japanese Society for Immunology
Distant interactions between dimorphisms in HLA-DR4 radically affect recognition of defined peptides by a specific T cell clone
Neurosciences Group, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK
1 Department Biochemistry and Molecular Biology, University College London, WC1 6BT, UK
2 Anergen Inc., Redwood City, CA 94063, USA
Correspondence to: N. Willcox
Several isolated dimorphisms recur in many HLA class II alleles, but it is not clear whether they merely influence the binding of peptides locally or have more general effects on their recognition by T cells. For example, interchanges in HLA-DRß include 86Gly 
Val and 57Asp Ser at either end of its 
helix, and 71Arg Lys in the middle. In DR4, the existence of six subtypes differing by single substitutions at these sites enabled us to assess their functional effects—both in isolation and in their natural context—on peptide presentation to a specific T cell clone with unusually broad cross-restrictions. Unexpectedly, the restriction imposed by 86Val was much more severe in the context of 71Arg than 71Lys, but was also more readily overcome by reducing the bulk of the `p1' peptide `anchor' residue (149Trp 
Phe). Moreover, when there was also a distant 57AspSer substitution, compensating similarly for 86Val proved much more difficult. Thus 86Val and 57Ser in combination had far more drastic effects on peptide presentation than they did separately, when peptide binding was also largely unchanged. These and other interactions with position 71 together provide strong evidence that the configuration of the peptide–DR4 complex is critical for T cell recognition, which could be affected by subtle conformational influences on the p1–9 core of the peptide or on the helix of DR4ß (between positions 86 and 57). Ideally, therefore, the effects of individual class II substitutions should be considered in their natural context rather than in isolation.
Keywords: autoimmunity, HLA-DR4, MHC polymorphism, peptide presentation, rheumatoid arthritis, T cell recognition
Transmitting editor: E. Simpson
3 Present address: Department Neurology, Kawatana National Hospital, Nagasaki 859-36, Japan
4 Present address: Department of Clinical Neuroscience, Charing Cross Hospital, London W6 8RF, UK
5 Present address: Department of Clinical Neuroscience, 339 Windermere Road, London, Ontario N6A 5A5, Canada
6 Present address: Megabios Corp., 863A Mitten Road, Burlingame, CA 94010, USA
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