Generation of Melanoma-Specific, Cytotoxic CD4+ T Helper 2 Cells: Requirement of both HLA-DR15 and Fas Antigens on Melanomas for Their Lysis by Th2 Cells

Recognition of melanoma antigens by HLA class-II-restricted CD4+ T lymphocytes has been investigated. Two cytotoxic CD4+ T cell lines were established by stimulating PBLs from a melanoma patient with either parental or IFN-γ-transduced autologous tumor cells. These T cells secreted IL-4, but not IL-2, IFN-γ, or TNF-β, in response to the autologous melanoma cells, suggesting that they belong to the Th2 subtype. Their cytotoxicity was directed against the IFN-γ-transduced melanoma cells and was HLA-DR-restricted. The autologous and two allogeneic IFN-γ-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-matched allogeneic melanoma cell lines, displaying low levels of HLA-DR antigens, induced Th2 proliferation and cytokine release, but were insensitive to lysis prior to upregulation of HLA-DR and Fas antigens by IFN-γ. Cytolysis 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.