The minimal polymorphism of class II E alpha chains is not due to the functional neutrality of mutations.
Given the extensive allelic amino acid sequence polymorphism present in the first domain of A alpha, A beta, and E beta chains and its profound effects on class II function, the minimal polymorphism in the mouse E alpha chain (and in its human homologue DR alpha) is paradox. Two possible explanations for the lack of polymorphism in E alpha are: (1) the E alpha chain plays such a uniquely critical structural/functional role in antigen presentation, T-cell activation, repertoire selection, and/or pairing with E beta or other proteins for expression that it cannot vary, and mutations are selected against; (2) the E alpha chain plays a less significant role than the outer domains of other major histocompatibility complex (MHC) proteins in determining the interactions with processed peptides or with T-cell receptor (TCR), so there is no selective pressure to maintain new mutations. To explore this question we compared the ability of transfectants expressing wild type (wt) E alpha E beta d and mutant E alpha wt E beta d proteins to present peptides and bacterial superantigens to T-cell hybridomas. Mutations at the E alpha amino acid positions 31, 52, and 65&66, to residues that represent allelic alternatives in A alpha chains, significantly reduced activation of peptide-specific T hybridomas, and mutations at 71 sometimes enhanced T-cell stimulation. None of the E alpha mutations reduced, and some enhanced, superantigen stimulation of T-cell hybridomas. These results argue against the hypothesis that E alpha chains are minimally polymorphic because mutations in E alpha are functionally neutral.
Chu
Z T
ZT
Department of Biological Sciences, Stanford University, CA 94305.
Carswell-Crumpton
C
C
Cole
B C
BC
Jones
P P
PP
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D006684:HLA-DR Antigens / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D006825:Hybridomas; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D017386:Sequence Homology, Amino Acid; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D018089:Superantigens