Structural features of autoreactive TCR that determine the degree of degeneracy in peptide recognition

Structural aspects of human TCRs that allow the activation of autoreactive T cells by diverse microbial peptides were examined using two human myelin basic protein (MBP)-specific T cell clones. The TCR sequences of these clon es differed only in the N region of TCR-alpha and -beta since the clones ha d the same V alpha-J alpha and V beta-J beta rearrangements. The two clones had a similar fine specificity for the MBP peptide, except for the P5 posi tion of the peptide (lysine), In the crystal structure of the HLA-DR2/MBP p eptide complex, P5 lysine is a prominent, solvent-exposed residue in the ce nter of the DR2/MBP peptide surface. Five microbial peptides with conservat ive or nonconservative changes at the P5 position (lysine to arginine, seri ne, or proline) activated one of these clones. In contrast, the other clone was activated only by three of these peptides which had a conservative lys ine to arginine change at P5, The degree of specificity/degeneracy in recog nition of the P5 side chain was the key difference between these TCRs since the Escherichia coli/Haemophilus influenzae peptide stimulated both clones when the P5 position was substituted from serine to arginine, These result s demonstrate that the complementarity-determining region 3 loops contribut e to the degree of degeneracy in peptide recognition by human MBP-specific TCRs.