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 molecule¹. 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-2^k strains of mice^2,3. This peptide binds with a K^d of ˜3 μM to I-A^k molecules¹. We have already ascertained that (1) the 10-mer HEL(52–61) is the shortest stimulatory peptide⁴; (2) the Leu⁵⁶ residue, the only residue different from mouse lysozyme, is responsible for the immunogenicity⁴; (3) the Leu⁵⁶ and Tyr⁵³ residues are critical for recognition by the T-cell receptor⁵ and (4) HEL(46–61) generates multiple determinants when it associated with the I-A^k molecule^4,6. 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^7,8. The two sites do not appear to be laterally separable in this peptide⁵ 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-A^k molecule. From modelling studies we also propose that HEL(52–61) assumes an α-helical conformation as it is bound to I-A^k and recognized by the T-cell receptor.