Identification of the T-cell and Ia contact residues of a T-cell antigenic epitope

Abstract

The precise molecular structure of the antigenic determinant recognized by the T-cell receptor of the CD4-positive cell has not been completely resolved. A major advance in our understanding of this issue has been made by our demonstration of a direct association between an immunogenic peptide and a purified Ia molecule. The most likely and economical hypothesis is that antigen binds directly to an Ia molecule creating the antigenic determinant and that this antigen-Ia complex is recognized by the T-cell receptor. We examined in detail a determinant of hen egg-white lysozyme (HEL) contained in the tryptic fragment HEL(46-61), recognized by T cells in H-2k strains of mice. This peptide binds with a Kd of approximately 3 microM to I-Ak molecules. We have already ascertained that (1) the 10-mer HEL(52-61) is the shortest stimulatory peptide; (2) the Leu56 residue, the only residue different from mouse lysozyme, is responsible for the immunogenicity; (3) the Leu56 and Tyr53 residues are critical for recognition by the T-cell receptor and (4) HEL(46-61) generates multiple determinants when it associated with the I-Ak molecule. If antigen and Ia interact, the antigen must have two features: it must bind to an Ia molecule and also interact with the T-cell receptor. The two sites do not appear to be laterally separable in this peptide and are therefore probably composed of distinct but interspersed amino-acid residues. We have now identified the three residues of HEL(52-61) that contact the T-cell receptor and three other residues that contact the I-Ak molecule. From modelling studies we also propose that HEL(52-61) assumes an alpha-helical conformation as it is bound to I-Ak and recognized by the T-cell receptor.

Inhibition of altered peptide ligand‐mediated antagonism of human GAD65‐responsive CD4+ T cells by non‐antagonizable T cells

“…However, two of the APL were capable of antagonizing five out of the six hGAD65 (555-567)-responsive clones. These two APL have substitutions at the p5 position, a major contact site for TCR recognition of MHC-peptide [24][25][26]. The finding that no single APL was able to antagonize all six clones and that many were agonistic is similar to findings on MBP APL [27].…”

Conformation of a T cell stimulating peptide in aqueous solution

“…On the basis of statistical analysis it has been suggested that immunodominant sites in T cell stimulating peptides have a high conformational propensity [19] and several workers have proposed that the ability to form secondary structure is important for antigenicity [20][21][22][23][24][25][26]. In particular, Berzofsky and co-workers [27] have shown that 18 out of 22 known immunodominant helper T cell epitopes correspond to sequences that are predicted to form stable amphipathic helices.…”

Human and Murine CD4 T Cell Reactivity to a Complex Antigen: Recognition of the Synthetic Random Polypeptide Glatiramer Acetate

“…Second, tyrosine, glutamic acid, and lysine residues are preferentially found in consensus binding sequences for DR molecules and can be accommodated in the MHC class II pockets as anchor residues. Third, in many cases, these residues have also been found to function as primary TCR contact residues (30,31). Due to the particularly high content in lysine, GA is likely to interact with a subset of T cells with accumulation of polar, acidic amino acid residues in the CDR3 region (32).…”