Response of a human T cell clone to a large panel of altered peptide ligands carrying single residue substitutions in an antigenic peptide: characterization and frequencies of TCR agonism and TCR antagonism with or without partial activation.
A CD4+ human T cell clone YN5-32 recognized a streptococcal M12p54-68 peptide in the context of HLA-DR4 and produced a large amount of IFN-gamma. We investigated responses of YN5-32 to 156 independent analogue peptides carrying single residue substitutions at residues 57 (position 1 (p1)) to 65 (p9) of the peptide. Approximately 30% of analogues at either Leu57 (p1), Ala60 (p4), or Asn62 (p6) residues exhibited TCR agonism to stimulate various magnitudes of proliferative responses in the T cell clone, and analogues exhibiting TCR antagonism are rare in these three residues. In analogues at either Glu58 (p2), Gln59 (p3), Tyr61 (p5), or Glu63 (p7) residue, 30 to 50% exhibited TCR antagonism. About 10% of analogues at Glu58 (p2) or Tyr61 (p5) stimulated proliferative responses, while 30 to 50% of analogues at Gln59 (p3) or Glu63 (p7) did so. Some of these TCR antagonistic analogues carrying relatively conservative amino acid substitutions partially activated the T cells to induce large increases in size and expression levels of CD4, CD11a (LFA-1), CD28, CD49d (VLA-4), and CD95 (Fas), and small increases in CD25 and CD44 expressions on the cell surface. None of the partially activating antagonistic analogues induced IFN-gamma production or anergy in T cells. Analogues with replacements of acidic amino acids at either Leu64 (p8) or Ser65 (p9) residue had dominant negative effects on T cell proliferation. Thus, altered peptide ligands with single residue substitutions in the antigenic peptide frequently stimulated the human T cell clone, in at least three different ways to exhibit agonism, antagonism, and antagonism with partial activation. Frequencies of analogue peptides exhibiting these three different effects on the T cell clone differed depending on the residue of the peptide substituted. Altered T cell responses induced by analogue peptides of a T cell epitope provide a system to analyze activation signals mediated by TCR, and to manipulate T cell responses.
Department of Neuroscience and Immunology, Kumamoto University Graduate School of Medical Sciences, Japan.
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Chen
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Matsushita
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Nishimura
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology*; D015703:Antigens, CD / Q000096:biosynthesis; D048429:Cell Size; D015804:HLA-DR4 Antigen / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013329:Structure-Activity Relationship; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
D000942:Antigens, Bacterial; D015703:Antigens, CD; D015804:HLA-DR4 Antigen; D008024:Ligands; D010446:Peptide Fragments; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma