Structural requirements of peptide and MHC for DR(alpha, beta 1*0401)-restricted T cell antigen recognition.
We identified functionally important regions of the DR(alpha, beta 1*0401) peptide binding site and present a model of bound peptide. DR(alpha, beta 1*0401)-restricted T cell recognition and peptide binding of Mycobacterium leprae (ML) peptide 38-50 and overlapping peptides from the 18-kDa heat-shock protein were analyzed. ML38-50 is unusual in its restricted binding pattern, binding to only one of five DR4 subtypes and no other DR molecules tested. Amino acid substitutions were introduced into ML38-50 and the DR(alpha, beta 1*0401) peptide binding site at positions likely to influence peptide-MHC or peptide- or MHC-TCR interactions. Peptide binding, T cell proliferation, and computer modeling studies suggest that residues 39F, 42E, and 44D of ML38-50 interact with pockets 1, 4, and 6, respectively, of the peptide binding site. Only DR(alpha, beta 1*0401) substitutions at residues in pockets 4 or 7 prevented binding of ML38-50, while multiple substitutions at other positions negatively affected its T cell recognition. In contrast, T cell recognition of some high affinity ML peptides that overlapped ML38-50, and contained N-terminal extensions, was only abolished with pocket 4 substitutions. An inverse correlation of peptide affinity for DR(alpha, beta 1*0401) with negative effects of MHC substitutions on T cell recognition of the overlapping ML peptides was observed. Thus, some regions, such as pocket 4, dominantly influence T cell recognition of multiple DR(alpha, beta 1*0401)-binding peptides. However, each DR(alpha, beta 1*0401)-binding peptide appears to have unique properties that determine the outcome of its MHC-peptide interactions and the relative importance of other polymorphic pockets.
McNicholl
J M
JM
Immunology Branch, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
Whitworth
W C
WC
Oftung
F
F
Fu
X
X
Shinnick
T
T
Jensen
P E
PE
Simon
M
M
Wohlhueter
R M
RM
Karr
R W
RW
D000595:Amino Acid Sequence; D001327:Autoimmune Diseases / Q000276:immunology; D001665:Binding Sites; D006684:HLA-DR Antigens / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009166:Mycobacterium leprae / Q000276:immunology; D010446:Peptide Fragments / Q000378:metabolism*; D017433:Protein Structure, Secondary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*; D014612:Vaccines / Q000276:immunology
D006684:HLA-DR Antigens; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D014612:Vaccines