It was once considered that the T cell response is an all or nothing type event, but recent studies have clearly indicated that T cells show many different types of activation in recognition of altered ligands for T cell receptors (TCR). In this review, we summarize our recent findings on the response of human CD4+ helper T (Th) cell clones to altered peptide ligands (APL); peptides carrying single or multiple residue substitutions in antigenic peptides. The extensive analyses revealed that TCR-antagonism and partial agonism are frequently observed by the stimulation with APLs substituted at particular amino acid residues of antigenic peptides. We observed unique partially agonistic APLs inducing prolongation of T cell survival without cell proliferation. Superagonistic APLs stimulated enhanced proliferation and production of cytokines in Th cell clones reactive to tumor-associated antigens. The other APL induced enhanced production of interleukin-12 by antigen presenting cells and subsequent enhancement of IFN-gamma production by T cells reactive to allergens. By utilizing an HLA-DR-restricted T cell epitope library generated by mutated invariant chain genes, it was revealed that human Th cell clones recognize a more diverse array of peptides with multiple and simultaneous amino acid substitutions in an antigenic peptide. APLs also induced altered intracellular signaling events including intracellular calcium increase and phosphorylation of signaling molecules. This information provides basic knowledge regarding the characteristics of antigen recognition by human Th cells and the subsequent activation, and a novel method for manipulation of human Th cell responses by APLs, as a possible candidate for antigen-specific immuno-potentiating or immunosuppressive therapy.