ACTIVATION of CD4+ T helper cells results from the occupancy of the T-cell receptor (TCR) by immunogenic peptide bound to a class II major histocompatibility complex (MHC) molecule1, together with a co-stimulatory signal from the antigen-presenting cell (APC)2. This activation leads to proliferation, cytokine production (Th1 or Th2 profile) and cytolysis3. Engagement of the TCR in the absence of co-stimulation causes Th1 cells to become unresponsive to subsequent antigenic stimulation 4-6. We have previously demonstrated that analogues of an immunogenic peptide could stimulate Th1 and Th2 cells to carry out some effector functions without inducing proliferation7,25, a phenomenon we term partial activation. Here we study the consequences of such partial activation through the TCR of two Th1 clones using peptide analogues presented by a live APC. A peptide analogue that is unable to stimulate clonal proliferation or production of cytokine or inositol phosphate can induce the T cells to become profoundly unresponsive to subsequent stimulation with the immunogenic peptide. Thus, altering the ligand of the TCR by using a peptide analogue on a functional APC sends a signal to Th1 clones that results in anergy.