Generation of Melanoma-Specific, Cytotoxic CD4 super(+) 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 super(+) T lymphocytes has been investigated. Two cytotoxic CD4 super(+) T cell lines were established by stimulating PBLs from a melanoma patient with either parental or IFN- gamma -transduced autologous tumor cells. These T cells secreted IL-4, but 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 was 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 super(+) 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- gamma . 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 super(+)-mediated lysis. Copyright 2001 Academic Press.