Critical role for the Val/Gly86 HLA-DR beta dimorphism in autoantigen presentation to human T cells.
Helper T lymphocytes recognize fragments of foreign (or self) antigens in the peptide-binding clefts of major histocompatibility complex class II molecules; their activation is a crucial step in the induction of many immune and autoimmune responses. While studying the latter, we raised a T-cell line from the thymus of a myasthenia gravis patient against recombinant alpha subunit of the human acetylcholine receptor, the target of this autoimmune disease. The line responds to the 144-156 region of the human sequence and not to the same region of the electric fish homolog, which differs by only three residues. These CD4+ T cells recognize this epitope only in the context of HLA-DR4 class II molecules, of which the variants with Gly86 are absolutely required. Thus the naturally occurring alternatives Dw14.2 (Gly86) and Dw14.1 (Val86)--which differ only at this one position in the entire antigen-binding region--show an all-or-nothing difference in presenting activity. This dimorphism at position 86 is widespread, occurring in subtypes of DR1, DR2, DR3, DR5, and DR6 alleles as well as DR4. Since other DR4 subtypes with substitutions at positions 70-74 also fail to present this peptide, and glycine residues can be uniquely flexible, we suggest that this replacement at position 86 acts locally or at a distance by altering the conformation of the peptide-binding cleft. Such profound functional consequences for T-cell recognition as we report here may explain this example of conserved major histocompatibility complex diversity.
Ong
B
B
Institute of Molecular Medicine, John Radcliffe Hospital, United Kingdom.
Willcox
N
N
Wordsworth
P
P
Beeson
D
D
Vincent
A
A
Altmann
D
D
Lanchbury
J S
JS
Harcourt
G C
GC
Bell
J I
JI
Newsom-Davis
J
J
D000293:Adolescent; D000483:Alleles; D000818:Animals; D000911:Antibodies, Monoclonal; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D002478:Cells, Cultured; D000939:Epitopes / Q000032:analysis; D014644:Genetic Variation; D005998:Glycine; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D008285:Major Histocompatibility Complex; D011950:Receptors, Cholinergic / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014101:Torpedo; D014633:Valine
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D000939:Epitopes; D006684:HLA-DR Antigens; D011950:Receptors, Cholinergic; D014633:Valine; D005998:Glycine