CD4+ T cells play an important role for tumor immunity in animal tumor models, yet there are few reports about the role of CD4+ HLA class II-restricted T cells in the immune response against human tumors. Against a human sarcoma exclusively CD4+, T cell clones could be established. These T cell clones were cytotoxic and secreted TNF and additional cytokines in response to the IFN-gamma-treated, HLA class II-positive autologous sarcoma cells. Several Ags were recognized by representative T cell clones: an Ag presented by HLA-DR and specific for the sarcoma; Ags presented by both HLA-DR alleles of the sarcoma, HLA-DR4 and -15, and shared by allogenic HLA-DR matched cell lines of different tissue lineages, including B cell blasts; and a sarcoma Ag presented by HLA-DP or DQ. Cytokine profiles of sarcoma-reactive T cell clones were dependent on the cytokine environment present during establishment of the T cell clones. The addition of exogenous IL-4 shifted the cytokine patterns of sarcoma-reactive T cell clones from Th1-like patterns to Th0/Th2-like patterns and decreased IL-10 production. TNF, IFN-gamma, IL-4, and supernatants of T cell clones induced HLA-DR expression on the sarcoma cells and, thus, were able to enhance Ag presentation. This autologous T cell response to a human sarcoma represents a new model for HLA class II-restricted T cell responses to human tumors.