Differing conditions of antigen priming varying either the concentration or affinity of T cell receptor (TCR) ligands greatly alter T cell responses. Here, we demonstrate that antigen-specific CD4(+) naive T cells primed with either altered peptide ligands (APLs) or a minimal concentration of antigen peptide become anergic without observable cell divisions. Transforming growth factor-beta1 (TGF-beta1) expression was induced 24 It following in these stimulation conditions producing anergic cells. Productively stimulated naive T cells expressed IL-2 to differentiate into T helper I (Thl) cells, secreting interferon-gamma (IFN-gamma) upon secondary antigen stimulation; T cells primed with an APL did not secrete either interleukin-4 (IL-4) or IFN-gamma, but expressed TGF-beta1 and Tob, a member of the anti-proliferative gene family. Therefore, T cell responses are regulated by TCR signaling depending on the extent of TCR engagement. These results suggest that partial antigen stimulation in the periphery can induce naive CD4(+)T cell unresponsiveness. (C) 2002 Elsevier Science (USA). All rights reserved.