Single Amino Acid Substitutions Within the HLA DR4β1 Chain Create Multiple T-Cell Recognition Sites
The ability of major histocompatibility complex (MHC) class II molecules to specifically bind antigenic peptides defines their role as immune response genes (1,2). To study the relationship between polymorphic specificities on class II molecules and T-cell function we have used alloreactive human T-cell clones. Utilizing a panel of T-cell clones we have dissected T-cell epitopes expressed by the five different subtypes of the HLA-DR4 family. HLA-DR4 alleles are characterized by a limited sequence polymorphism residing within the third hypervariable region of the HLA-DRβ1 chain (3,4). Correlation of T-cell reactivities to allele-specific amino acid substitutions allowed the molecular mapping of a number of T-cell determinants encoded within the third hypervariable region of the β1 chain. A segment of 15 amino acids spanning positions 71 to 86 appears to be crucially involved in the formation of multiple T-cell epitopes. An extraordinary diversity for T-cell responses is created by substitutions at residues 71, 74, and 86, each of which contributes equally to a cluster of overlapping T-cell recognition sites. These data provide evidence that single amino acids within the third hypervariable region play a critical role for the three-dimensional structures recognized as T-cell receptor ligands and that a limited sequence polymorphism can induce multiple sites that differentially stimulate individual T lymphocytes.
KeywordsPolypeptide Stein Thymidine
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- 3.Gregerson PK, Shen M, Song Q, Merryman P, Degar S, Sehi T, et al. Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci USA 1986; 83: 2642.Google Scholar
- 6.Goronzy J, Weyand CM, Fathman CG. Cloning of human alloreactive T-cells. In: Sabato G, (ed): Methods in Enzymology. Immunochemical Techniques. New York, Academic Press, in press.Google Scholar
- 10.Germain RW, Ashwell JD, Lechler RI, Margulies DH, Nickerson RM, Suzuki G, et al. “Exon shuffling” maps control of antibody-and T-cell-recognition sites to the NH2-terminal domain of the class II major histocompatibility polypeptide A. Proc Natl Acad Sci, USA 1985; 82: 2940.Google Scholar