REGULATORY ROLE OF CD8 IN MAJOR HISTOCOMPATIBILITY COMPLEX-UNRESTRICTED TUMORICIDAL ACTIVITY OF MOUSE T-CELLS ACTIVATED WITH ANTI-CD3 MONOCLONAL-ANTIBODY

Antigen-nonspecific CD8(+) cytotoxic T cells induced with anti-CD3 mon oclonal antibody (mAb) are able to kill tumor cells in a major histoco mpatibility complex (MHC)-unrestricted fashion. However, the role of C D8 in the MHC-independent tumoricidal activity of anti-CD3-activated k iller T (AK-T) cells has not been investigated. Here we show that anti -CD8 alpha mAb inhibits, in a dose-dependent fashion, lysis of P815 an d YAC-1 tumor cells by mouse AK-T cells. The inhibition of MHC-unrestr icted cytotoxicity by anti-CD8 alpha mAb cannot be attributed to inter ference with an adhesion-like function of CD8 towards class I MHC mole cules on the target cells because anti-CD8 alpha mAb (i) had equal inh ibitory effects on the cytolysis of tumor target cells regardless of t heir relative level of class I MHC molecule expression and (ii) did no t interfere with the formation of conjugates between AK-T cells and cl ass I MHC-bearing P815 tumor cells. However, anti-CD8 alpha mAb abroga ted AK-T cell granule exocytosis in the presence of P815 tumor cells, indicating a regulatory role for CD8 in the signal transduction events which result in lysis of the tumor target cell. Immunoblot analysis o f the post-nuclear fraction of lysates from AK-T cells exposed to P815 tumor cells in the presence of anti-CD8 alpha mAb revealed reduced ph osphorylation of tyrosine residues on a protein with an Mr of similar to 62 kDa. Taken together, these data suggest that CD8 is able to affe ct the tumoricidal activity of MHC-unrestricted AK-T cells independent of class I MHC molecules on the target cell.