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) molecule, together with a co-stimulatory signal from the antigen-presenting cell (APC). This activation leads to proliferation, cytokine production (Th1 or Th2 profile) and cytolysis. Engagement of the TCR in the absence of co-stimulation causes Th1 cells to become unresponsive to subsequent antigenic stimulation. We have previously demonstrated that analogues of an immunogenic peptide could stimulate Th1 and Th2 cells to carry out some effector functions without inducing proliferation, 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.