Polymorphic residues on the I-A beta chain modulate the stimulation of T cell clones specific for the N-terminal peptide of the autoantigen myelin basic protein.
The effect of polymorphic residues on the A alpha A beta molecule on T cell recognition of the N-terminal nonapeptide of myelin basic protein (R1-9) was determined. Ak-restricted T cell clones recognizing R1-9 were isolated. The peptide-Ia specificities of these clones were determined by testing the response to 1) a panel of peptide analogs of R1-11, 2) splenic APC from mice expressing MHC molecules from serologically distinct haplotypes, and 3) L cell transfectants expressing mutant/recombinant A beta cDNA containing combinations of polymorphic nucleotide sequences from the k and u alleles. Comparisons were made between the Ak-restricted clones and a previously characterized panel of Au-restricted clones. Certain Ak-restricted clones were able to recognize MBP peptide analogs that were not recognized by any of the Au-restricted clones. The Au-restricted T cell clones did not cross-react with R1-9 presented in the context of Ak, whereas the majority of the Ak-restricted clones responded to R1-9 presented in the context of Au. This nonreciprocal cross-reactivity was also reflected in the relative responses of the two sets of T cell clones to the interchange of u- and k-derived residues in the A beta chain. Residues in regions corresponding both the alpha-helical or beta-sheet portions of the hypothetical Ia three-dimensional structure were involved. The results suggest that overall specificity of the T cell clones is the summation of numerous distinct subspecificities for different regions of the peptide-Ia ligand. These results indicate that there can be striking differences in T cell specificity for an autoantigenic epitope, even in the context of A alpha A beta molecules from very closely related haplotypes.
Davis
C B
CB
Department of Biological Sciences, Stanford University, CA 94305-5020.
Mitchell
D J
DJ
Wraith
D C
DC
Todd
J A
JA
Zamvil
S S
SS
McDevitt
H O
HO
Steinman
L
L
Jones
P P
PP
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D002469:Cell Separation; D002999:Clone Cells / Q000276:immunology; D000939:Epitopes / Q000235:genetics; D005260:Female; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007739:L Cells; D008213:Lymphocyte Activation; D051379:Mice; D008805:Mice, Inbred A; D008969:Molecular Sequence Data; D009154:Mutation; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D001324:Autoantigens; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D010455:Peptides; D011994:Recombinant Proteins