ALTERED HAPTEN LIGANDS ANTAGONIZE TRINITROPHENYL-SPECIFIC CYTOTOXIC T-CELLS AND BLOCK INTERNALIZATION OF HAPTEN-SPECIFRE RECEPTORS

Low molecular chemicals (haptens) frequently cause T cell-mediated adv erse immune reactions. Our previous work provided evidence that hapten -specific T cells, in analogy to those specific for nominal peptide an tigens, direct their TCR towards hapten-modified, MHC-associated pepti des. We now demonstrate that trinitrophenyl (TNP)-specific, class I MH C-restricted CTL from mice may exhibit exquisite specificity for subtl e 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 molecul ar basis of T cell antagonism. Whereas agonists resulted in a dose-dep endent downregulation of TCR in different mouse T cell clones, antagon istic peptides totally failed to do so despite engaging the specific T CR. Moreover, simultaneous presentation of antagonist and agonist on t he same antigen presenting cell prevented TCR internalization. No sign s of anergy or functional receptor inactivation were observed in CTL t reated with antagonist-loaded target cells. Based on a serial triggeri ng model of T cell activation, our data favor a model in which antagon ists block T cell functions by competitively engaging the specific TCR in unproductive interactions.