We have established several tumor T cell lines, both from the skin and from the blood of a patient with an MHC class II-/class I+, CD4+ cutaneous T cell lymphoma (CTCL). These cell lines, like the initial tumor cells, had a CD3+CD4+CD8- phenotype. We also isolated two cytotoxic T lymphocyte clones from the tumor site of this CTCL patient. These clones displayed a CD4+CD8dim+ (TC5) and CD4+CD8- (TC7) phenotype and mediated a specific MHC class I-restricted cytotoxic activity toward noncultured tumor cells and autologous tumor cell lines. Despite surface expression of Fas on tumor cells and Fas-L induction on TC5 and TC7 cell membrane after coculture with autologous tumor cells, the CD4+ CTL clones did not use this cytotoxic mechanism to lyse their specific target. TC7 used a granzyme/perforin-dependent pathway, whereas TC5 used a TRAIL-dependent mechanism. Quantitative analysis of cytokine mRNA expression indicated that while the tumor cells displayed a Th2-type profile, the CTL clones expressed Th1-type cytokines. Preincubation of TIL clones with autologous tumor cells in a short-term culture induced their activation and subsequent amplification of the Th1-type response, which indicates a direct contribution of the malignant cells in the Th1/Th2 imbalance. However, we found that tumor cells produced high amounts of TGF-beta, which could explain the inhibition of a specific antitumor immune response. Another mechanism to avoid the host immune response was the expression of CD158a, CD158b, p70, and CD94/NKG2A inhibitory receptors by tumor-specific lymphocytes. Finally, we present recent data on new antigen structures expressed both by long-term CTCL lines and uncultured tumor cells.