Peptide length-dependent TCR antagonism on class II HLA-restricted responses of peripheral blood mononuclear cells and T cell clones

T cell clonal recognition of peptide ligands is highly diverse. To investigate how peptide mixtures with diverse sequences affect polyclonal responses of peripheral blood mononuclear cells (PBMC), we synthesized Xn (n = 9-19) peptides that consist of 9 to 19 residues with random sequences. We found that: (1) in antagonism assays, Xn peptides inhibit polyclonal responses of PBMC induced by purified protein derivative (PPD) and crude mite extracts as well as mixed lymphocyte reaction (MLR), in which intermediate-length peptides (n = 13 or 15) show the largest inhibitory effects; and (2) a high-affinity HLA-DR4-binding peptide is devoid of inhibitory activity against MLR to DR4, indicating that these effects are not caused by inhibition of peptide binding to HLA. Furthermore, X15 did not abrogate PBMC proliferation induced by phorbol 12-myristate 13-acetate + ionomycin, or anergize PBMC by preculture. All these observations indicate that TCR antagonism does exist at peripheral T cell levels in humans, and that Xn peptides, depending on peptide length, are capable of antagonizing T cell polyclonal responses. Indeed, even with cloned T cells, certain non-agonistic peptides shorter (but not too short) than the wild type in their C termini, function as TCR antagonists, findings which corroborate the observation that X13-15 antagonizes T cell responses more efficiently than does X17-19 or X9-11.