The Journal of Immunology, Vol 159, Issue 10 4943-4951, Copyright © 1997 by American Association of Immunologists

ARTICLES

Autoantigen recognition by human CD8 T cell clones: enhanced agonist response induced by altered peptide ligands

A Dressel, JL Chin, A Sette, R Gausling, P Hollsberg and DA Hafler
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Determination of immunodominant epitopes of MHC class I-restricted self- Ags and elucidation of TCR contact residues is of potential importance in providing a means of manipulating the immune response to self-Ags in human autoimmune diseases. A computer algorithm was used to examine the sequences of the two major encephalitogenic proteins of myelin, MBP and PLP, for HLA-A2 binding motifs. Thirty-eight peptides with HLA-A2.1 binding motifs were synthesized and their binding to HLA-A2.1 was measured. A panel of HLA-A2-restricted T cell clones directed against the PLPp80-88 epitope, which exceeded the binding affinity of the other myelin-peptides tested by at least one order of magnitude, was generated. Using a set of analogue peptides with single amino acid substitutions, we detected a distinct pattern of TCR contact residues for each clone. Surprisingly, modification of different presumed TCR contact residues generated superagonist peptides, which are defined as peptides with equal or lower MHC binding affinity to HLA-A2 that induce half-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 concentrations at which the native peptide induced only cytotoxic responses. The proliferation induced by the superagonist peptides gives additional evidence that the clonal expansion of CD8 T cell clones may in part be regulated on the level of Ag recognition by the TCR.

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