Inhibition of T cell activation can be mediated by analogs of the original
antigenic peptide (TCR antagonists). Here, a T cell clone expressing two di
stinct TCR was used to investigate whether such inhibition involves an acti
ve mechanism by examining whether an antagonist for one TCR could influence
responses stimulated by the other TCR engaging its agonist. Our results de
monstrate functional cross-inhibition under these conditions involving the
ability of antagonist: TCR interactions to diminish Lck enzymatic activity
associated with the agonist-recognizing second TCR, apparently through enha
ncement of SHP-1 association with these receptors. Our findings reveal that
inhibition of cellular responses by antagonists arises at least in part fr
om active negative regulation of proximal TCR signaling and identify elemen
ts of the biochemical process.