Altered hapten ligands antagonize trinitrophenyl-specific cytotoxic T cells and block internalization of hapten-specific receptors.
Low molecular chemicals (haptens) frequently cause T cell-mediated adverse immune reactions. Our previous work provided evidence that hapten-specific T cells, in analogy to those specific for nominal peptide antigens, direct their TCR towards hapten-modified, MHC-associated peptides. We now demonstrate that trinitrophenyl (TNP)-specific, class I MHC-restricted CTL from mice may exhibit exquisite specificity for subtle structural details of these hapten determinants, surpassing even the specificity of immunoglobulins. More importantly, these CTL could be antagonized by ligands altered either in their peptide sequence or in their hapten structure. The system was employed to examine the molecular basis of T cell antagonism. Whereas agonists resulted in a dose-dependent downregulation of TCR in different mouse T cell clones, antagonistic peptides totally failed to do so despite engaging the specific TCR. Moreover, simultaneous presentation of antagonist and agonist on the same antigen presenting cell prevented TCR internalization. No signs of anergy or functional receptor inactivation were observed in CTL treated with antagonist-loaded target cells. Based on a serial triggering model of T cell activation, our data favor a model in which antagonists block T cell functions by competitively engaging the specific TCR in unproductive interactions.
Preckel
T
T
Max-Planck-Institut für Immunbiologie, Stübeweg 51, D-79108 Freiburg, Germany.
Grimm
R
R
Martin
S
S
Weltzien
H U
HU
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D004247:DNA / Q000096:biosynthesis; D006241:Haptens; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000276:immunology* / Q000494:pharmacology; D010851:Picrates; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D013936:Thymidine / Q000378:metabolism
D006241:Haptens; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D009842:Oligopeptides; D010851:Picrates; D011948:Receptors, Antigen, T-Cell; D004247:DNA; C005858:picric acid; D013936:Thymidine