Cell-mediated cytotoxicity to SV40-specific tumour-associated antigens

Abstract

CYTOTOXIC thymus-derived lymphoctyes (T cells) from mice infected with lymphocytic choriomeningitis virus, ectromelia virus, vaccinia virus, or parainfluenza virus interact only with H–2 compatible virus-infected target cells^1–6. When congenic H–2 recombinant mice⁷ and mice containing mutations within genes mapped at H–2K end specificities^6,8 are used, recognition of virus-infected target cells by the effector lymphocytes requires compatibility at either the K or D locus of the H–2 gene complex. These observations led to the hypothesis that cytotoxic T cells recognise either a complex of viral and histocompatibility antigens or virus-induced alterations of the histocompatibility antigens. The same restriction has been described for the cytotoxic T cell response to lymphocytes modified by trinitrophenyl (TNP)⁹, to minor histocompatibility antigens^10,11 and to the male Y antigen¹². To investigate the possibility of a similarly restricted specificity of the effector cells of cell-mediated immunity to tumours, cytotoxic cells specific for SV40 tumour-associated specific antigens (SV40-TASA) were generated in two inbred strains of mice, C57BL/6J and BALB/cAn. The SV40-transformed lines C57SV (SV40-transformed C57BL/6 mouse embryo fibroblasts), MKS/Bu100 (SV40-transformed BALB/c kidney cells¹³) and LN-SV (SV40-transformed human skin fibroblasts¹⁴) were used as immunising and target cells (Table 1). In addition, clones of human–mouse somatic cell hybrids, obtained by fusion of LN-SV and mouse peritoneal macrophages from inbred strains¹⁵ were used. These hybrid clones contain the complete mouse genome and, in addition, one to several copies of human chromosome 7, in which the SV40 genome is presumably integrated^14,15. C121, N8 and N9 cells are derived from LN-SV fused with C57BL/6 macrophages¹⁶ and C136 cells from LN-SV fused with BALB/c macrophages¹⁷. These clones express the SV40 tumour (T) antigen (a nuclear antigen)^16,17, and the histocompatibility antigens of the murine parental cells (our unpublished results). Neither LN-SV nor any hybrid clones derived from LN-SV make infectious SV40¹⁸. Only after fusion with permissive monkey kidney cells can some SV40 particles be rescued. This defective virus exhibits no biological activity. Both LN-SV and human–mouse somatic cell hybrids containing the human chromosome 7 derived from LN-SV exhibit tumour-specific transplantation antigens (TSTA), as demonstrated by their ability to protect SV40-inoculated newborn hamsters from developing SV40 tumours¹⁹. Both the SV40-transformed mouse cell lines (our unpublished results) and the hybrid clones^16,17 are tumorigenic in immunodeficient “nude” mice, but these cells do not grow routinely in immunocompetent syngeneic mice, probably because of strong TSTA²⁰.