Generation of melanoma-specific, cytotoxic CD4(+) T helper 2 cells: Requirement of both HLA-DR15 and Fas antigens on melanomas for their lysis by th2cells

Recognition of melanoma antigens by HLA class-II-restricted CD4(+) T lympho cytes has been investigated. Two cytotoxic CD4(+) T cell lines were establi shed by stimulating PBLs from a melanoma patient with either parental or IF N-gamma -transduced autologous tumor cells. These T cells secreted IL-4, bu t not IL-2, IFN-gamma, or TNF-beta, in response to the autologous melanoma cells, suggesting that they belong to the Th2 subtype. Their cytotoxicity w as directed against the IFN-gamma -transduced melanoma cells and was HLA-DR -restricted. The autologous and two allogeneic IFN-gamma -modified melanoma cell lines shared melanoma antigen(s) presented in the context of HLA-DR15 . HLA-DR15(+) nonmelanoma cells were resistant targets indicating that the shared antigen(s) is melanoma associated. Parental autologous and HLA-DR-ma tched allogeneic melanoma cell lines, displaying low levels of IIIA-DR anti gens, induced Th2 proliferation and cytokine release, but were insensitive to lysis prior to upregulation of IIIA-DR and Fas antigens by IFN-gamma. Cy tolysis was inhibited by anti-HLA-DR and by anti-Fas antibodies, suggesting that the cytolysis is mediated via the Fas pathway. While small amounts of HLA-DR15 molecules on melanoma cells are sufficient for Th2 proliferation and cytokine release, higher amounts of HLA-DR15 and the expression of Fas are required for CD4(+)-mediated lysis. (C) 2001 Academic Press.