Differential requirement of perforin and IFN-gamma in CD8 T cell-mediated immune responses against B16.F10 melanoma cells expressing a viral antigen

Perforin-mediated lysis and secretion of IFN-gamma belong to the key effect or functions of CD8 T cells. To compare the anti-tumor activity of these tw o mechanisms, we used B16.F10 mela- noma cells (B16(GP33)) expressing the c ytotoxic T cell epitope GP33 and T cell receptor transgenic (TCR-tg) mice s pecific for GP33 and deficient in perforin or IFN-gamma. B16(GP33) tumor ce lls, injected either i.v. to induce experimental metastases or s.c., were s imilarly controlled in both wild-type and perforin-deficient, but not in IF N-gamma-deficient TCR-tg mice. A similar result was obtained when the thera peutic efficacy of adoptively transferred TCR-tg effector cells from these mice was examined in the corresponding perforin- or IFN-gamma-deficient C57 BL/6 hosts. Criss-cross experiments further revealed that IFN-gamma product ion by the host strongly influenced the efficiency of the adoptively transf erred effector cells. In contrast to the potent ability of GP33-specific ef fector cells to mediate B16(GP33) tumor regression without perforin, GP33-s pecific memory cells, induced with recombinant vaccinia virus expressing GP 33, failed to control B16(GP33) tumor growth in the absence of perforin. In conclusion, our data demonstrate a crucial role for IFN-gamma in B16(GP33) tumor cell elimination in vivo and indicate a differential requirement of perforin by effector versus memory CD8 T cells in anti-tumor immunity.