A. Dressel et al., AUTOANTIGEN RECOGNITION BY HUMAN CD8 T-CELL CLONES - ENHANCED AGONISTRESPONSE INDUCED BY ALTERED PEPTIDE LIGANDS, The Journal of immunology, 159(10), 1997, pp. 4943-4951
Determination of immunodominant epitopes of MHC class I-restricted sel
f-Ags and elucidation of TCR contact residues is of potential importan
ce in providing a means of manipulating the immune response to self-Ag
s in human autoimmune diseases. A computer algorithm was used to exami
ne the sequences of the two major encephalitogenic proteins of myelin,
MBP and PLP, for HLA-A2 binding motifs. Thirty-eight peptides with HL
A-A2.1 binding motifs were synthesized and their binding to HLA-A2.1 w
as measured. A panel of HLA-A2-restricted T cell clones directed again
st the PLPp80-88 epitope, which exceeded the binding affinity of the o
ther myelin-peptides tested by at least one order of magnitude, was ge
nerated. Using a set of analogue peptides with single amino acid subst
itutions, we detected a distinct pattern of TCR contact residues for e
ach clone. Surprisingly, modification of different presumed TCR contac
t residues generated superagonist peptides, which are defined as pepti
des with equal or lower MHC binding affinity to HLA-A2 that induce hal
f-maximal effector responses at 100-fold lower concentrations than the
original peptide. These agonist peptides could drive cytotoxic T cell
clones to proliferate, secrete cytokines, and clonally expand at conc
entrations at which the native peptide induced only cytotoxic response
s. The proliferation induced by the superagonist peptides gives additi
onal evidence that the clonal expansion of CD8 T cell clones may in pa
rt be regulated on the level of Ag recognition by the TCR.