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

Abstract

Protective immunity of BALB/c mice immunized with simian virus 40 (SV40) large T antigen (TAg) against SV40-transformed, TAg-expressing mKSA tumor cells is critically dependent on both CD8؉ and CD4 ؉ T lymphocytes. By depleting mice of T-cell subsets at different times before and after tumor challenge, we found that at all times, CD4 ؉ and CD8 ؉ cells both were equally important in establishing and maintaining a protective immune response. CD4؉ cells do not contribute to tumor eradication by directly lysing mKSA cells. However, CD4؉ lymphocytes provide help to CD8 ؉ cells to proliferate and to mature into fully active cytotoxic T lymphocytes (CTL). Depletion of CD4؉ cells by a single injection of CD4-specific monoclonal antibody at 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 cytokines interleukin 2 (IL-2) and gamma interferon. Because in this system TAg-specific CD8؉ cells secrete only minute amounts of IL-2, it appears that T helper cells provide these cytokines for CD8 ؉ T cells. Moreover, this helper effect of CD4 ؉ T cells in mKSA tumor rejection in BALB/c mice does not simply improve the activity of TAg-specific CD8 ؉ CTL but actually enables 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 cell rejection in order to maintain protective immunity. However, despite the support of CD4 ؉ T helper cells, the tumor-specific CTL response is so weak 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.

An inducible transgenic mouse breast cancer model for the analysis of tumor antigen specific CD8+ T-cell responses

“…After injection of 10 6 mKSA cells, i.e. the ten-thousand-fold dose of tumor cells lethal for 50% of the mice [ 10 ], all naïve wtBALB/c mice (13/13 mice) succumbed to mKSA tumors within a mean survival time of 21 days (Table I ). Immunization by two sc injections of SV40 established long-term protection against mKSA tumors in almost all (12/13 mice) wt mice.…”

“…Nevertheless, protective cellular immunity against transplantable murine SV40 tumors can be achieved by pre-immunization with SV40 or purified T-Ag, which induces an efficient and long-lasting CD4 + helper T-cell dependent CTL response against established SV40 tumor cells (e.g. mKSA) [ 9 , 10 ]. As the T-Ag specific CTL response in BALB/c mice is weak, and as, furthermore, the major histocompatibility complex (MHC) class I H-2 d restricted T-Ag specific T-cell epitopes have not yet been characterized, the analysis of T-Ag specific CD8 + T-cell responses in BALB/c mice is technically difficult.…”

Tumor Immunity against a Simian Virus 40 Oncoprotein Requires CD8+T Lymphocytes in the Effector Immune Phase

“…with mKSA tumor cells (40). During the course of immunization and tumor cell challenge (i.e., the induction and effector phases), both CD4 ϩ and CD8 ϩ T-cell subsets were found to be required immunologic components to achieve protection from mKSA cell tumorigenic growth in vivo.…”

“…The requirement for CD8 ϩ T-cell activity against SV40 Tagexpressing mKSA tumor cells after recombinant SV40 Tag protein immunization has been reported previously (1,40,47). However, this is the first report detailing the requirement of CTL activity after the onset of mKSA tumor cell challenge (i.e., the effector-phase response) in an experimental pulmonary metastasis model.…”

A Role for Antibodies in Tumor Immunity

“…With regard to in vivo studies on the mechanism(s) of recombinant SV40 TagÀinduced immunity in murine tumor models, we are still of the opinion that antibodies and CD4 T cells share either a dual or interdependent role. Recently, studies using a different recombinant SV40 Tag preparation, the solid tumor model, and in vivo depletion of CD4 and CD8 cells, suggested that CD8 CTL are critical in SV40 TagÀinduced immunity and that the activation of these effector cells by CD4 T helper cells is the mechanism by which CTLs target the tumor cell [70]. Previously, these investigators proposed that CD8 T cells are the major effector mechanism and are required for tumor immunity in BALB=c mice induced by recombinant SV40 protein strategies [71].…”