The stimulation of activated T cells with soluble peptides or peptide-pulsed T-APC in the absence of professional APC can anergize peptide-specific T cells. Here, we studied human T cell clones (TCCs) that either proliferate (T-responder) or do not proliferate (T-nonresponder) to activated T cells as antigen-presenting cells (APC) and investigated the efficacy of anergy induction in these two types of TCCs. The TCCs were specific to the p30 peptide from tetanus toxoid and secreted either a Th0- or a Th1-like cytokine pattern. To induce anergy, the TCCs were first stimulated by addition of the peptides directly to the cell cultures without additional APC (T-APC). Anergy was detected by restimulating these TCCs on professional B-APC. The proliferation, production of cytokines (IL2, IFN-gamma, IL4, IL5, IL10), and the cytotoxicity were measured after the first and second stimulation and compared with nonanergized control cells. Priming of TCCs by T-APC (anergy induction) resulted in an elevated production of IL4. This cytokine shift was also seen in the T-nonresponder TCC despite no induced proliferation. Th1-like TCCs retained their cytotoxicity after anergy induction. In contrast to cells first activated by B-APC, the restimulation of TCCs primed by T-APC lead to a drastic reduction of proliferation and cytokine production for both T-responder and T-nonresponder TCCs. The functional down-regulation of TCCs mediated by soluble peptides could be overcome by addition of IL2, but not by IL1 or IL4. We concluded that the induction of T-cell anergy does not require cell proliferation.