Simian virus 40 large-T-antigen-specific rejection of mKSA tumor cells in BALB/c mice is critically dependent on both strictly tumor-associated, tumor-specific CD8(+) cytotoxic T lymphocytes and CD4(+) T helper cells

Protective immunity of BALB/c mice immunized with simian virus 40 (SV40) la rge T antigen (TAg) against SV40-transformed, TAg-expressing mKSA tumor cel ls is critically dependent on both CD8(+) and CD4(+) T lymphocytes. By depl eting mice of T-cell subsets at different times before and after tumor chal lenge, we found that at all times, CD4(+) and CD8(+) cells both were equall y important in establishing and maintaining a protective immune response. C D4(+) cells do not contribute to tumor eradication by directly lysing mKSA cells. However, CD4' lymphocytes provide help to CD8(+) cells to proliferat e and to mature into fully active cytotoxic T lymphocytes (CTL). Depletion of CD4(+) cells by a single injection of CD4-specific monoclonal antibody a t any time from directly before injection of the vaccinating antigen to up to 7 days after tumor challenge inhibited the generation of cytolytic CD8() lymphocytes. T helper cells in this system secrete the typical Th-1 cytok ines interleukin 2 (IL-2) and gamma interferon. Because in this system TAg- specific CDS' cells secrete only minute amounts of IL-2, it appears that T helper cells provide these cytokines for CD8(+) T cells. Moreover, this hel per effect of CD4(+) T cells in mKSA tumor rejection in BALB/c mice does no t simply improve the activity of TAg-specific CD8(+) CTL but actually enabl es them to mature into cytolytic effector cells. Beyond this activity, the presence of T helper cells is necessary even in the late phase of tumor cel l rejection in order to maintain protective immunity. However, despite the support of CD4(+) T helper cells, the tumor-specific CTL response is so wea k that only at the site of tumor cell inoculation and not in the spleen or in the regional lymph nodes can TAg-specific CTL be detected.