TUMOR-SPECIFIC CTL RESPONSE REQUIRING INTERACTIONS OF 4 DIFFERENT CELL-TYPES AND RECOGNITION OF MHC CLASS-I AND CLASS-II RESTRICTED TUMOR-ANTIGENS

This study demonstrates that a syngeneic specific cytotoxic T lymphocy te (CTL) response to a class I major histocompatibility complex (MHC) positive tumour requires dual processing and recognition of tumour ant igens. One type of antigen is processed and expressed in association w ith class I MHC at the surface of intact tumour cells. It is recognize d by CD8 alpha,beta TCR CTL in vitro and by protective immune T cells in vivo and thus functions as a tumour-associated transplantation anti gen (TATA). The other type of antigen is processed and expressed by di stinct host APC in association with class 11 MHC. This is recognized b y immune CD4 T cells which function as essential helper cells in the g eneration of the CD8 CTL response. These conclusions are supported by cell depletion and reconstitution experiments as well as by blocking e xperiments with monoclonal antibodies using the highly metastatic clas s II negative murine lymphoma ESb as a model system. The existence of two types of cognate T cell responses in a syngeneic anti-tumour respo nse was directly proved by the establishment of two types of tumour sp ecific T cell lines which required as co-stimulator either MHC class I I positive APC or IL-2. In suboptimal mixed lymphocyte tumour cell cul tures either of these co-stimulator functions was found to be limiting the overall anti-tumour CTL response. The generation of the tumour sp ecific CTL response could be blocked by monoclonal antibodies against all the molecules involved in the cognate interactions (i.e. class I M HC, CD8, class II MHC, CD4 and TCR) but not by anti-CD2 or and-IgG. Th e strict requirement for helper cells and APC could be bypassed by the addition of recombinant IL-2 but optimal triggering of CD8 CTL-precur sor required viable tumour stimulator cells. This well characterized i n vitro assay may be useful (i) for monitoring the immune status of CD 4 and CD8 immune T cells separately, for instance of tumour bearing an d/or treated animals and (ii) for the development and testing of poten t tumour cell vaccines with T cell stimulatory and/or co-stimulatory a ctivities.