Tumorigenicity of mouse T lymphoma cells is controlled by the level of major histocompatibility complex class I H-2Kk antigens

Abstract

We have previously found that an increased tumorigenicity and spontaneous metastatic potential of BW5147-derived T lymphoma cells was associated with a decrease in major histocompatibility complex (MHC) class I H-2Kk antigen expression. This suggested that H-2Kk antigens may control the tumorigenic potential of BW T lymphoma cells. Our current experiments aimed to prove this association by specifically altering H-2Kk expression by gene transfection. Transfected cells expressing a high level of H-2Kk antigens were significantly less tumorigenic and metastatic after subcutaneous inoculation. However, there was selection in vivo for cells expressing a reduced level of H-2Kk antigens, which concomitantly led to an increased tumorigenicity. These data further confirmed the strong association between H-2Kk expression and tumorigenicity. We subsequently tested whether the immune system is implicated in this phenomenon by inoculating the H-2Kk transfectants into irradiated, immunocompromised recipients. Our results indicate that the reduced tumorigenicity of the BW H-2Kk transfectants is due to an immune rejection mechanism, mediated by CD8+ immune effector cells, as revealed by in vivo depletion experiments with anti-CD8 antibodies. Hence, we hereby demonstrated that H-2Kk antigens increased the immunogenicity of BW cells, via a CD8-dependent mechanism, which consequently reduced their tumorigenicity.

Antagonistic effect of NK cells on alternatively activated monocytes: a contribution of NK cells to CTL generation

“…Because BW-Sp3 tumor rejection relies on both CD8 ϩ cytolytic T cells 40,41,49 and NK cells (see earlier section), the role of NK cells in early antigen-specific CTL activity in tumor-bearing mice was investigated. Splenocytes of tumor-inoculated immunocompetent and NK-depleted mice were restimulated in vitro and subsequently tested for their CTL activity.…”

“…49 We have demonstrated previously that CD8 ϩ T cells are the critical immune effectors involved in the control of BW-Sp3 tumorigenicity. 40,41,49 To investigate the importance of NK cells in early local antitumor immune responses, AKR mice were treated with ␣-ASGM-1. In first instance, we verified the NK-specific effect of this treatment in the spleens of naive mice versus those of tumor-bearing mice 8 days after tumor injection, of which the latter are expected to contain activated tumor-specific CTL.…”

“…Hereby, the BW-Sp3 lymphoma model was adopted because rejection of BW-Sp3 depends on eliciting strong CTL responses, 40,41 and consequently this model allowed us to examine the involvement of NK cells in early CD8 ϩ -dependent immune reactions. To address the importance of NK cells for the early antitumor defense, ␣ asialo GM 1 (␣-ASGM-1)-treated mice were challenged with BW-Sp3 cells.…”

Variation in H-2Kk peptide motif revealed by sequencing naturally processed peptides from T-cell hybridoma class I molecules

“…Early studies evaluating alterations in class I molecules in the ultraviolet-induced fibrosarcoma C3H implicated the MHC class I H-2Kk molecule in neoplastic progression (Hartley et al, 1977;Linsk et al, 1986). More recent studies have directly connected MHC class I H-2Kk as one of the key factors in neoplastic potential of cell lines transformed with MuLV (VandenDriessche et al, 1994). Downregulation and decreased expression of H-2Kk using antisense RNA results in increased oncogenicity of the AKR thymoma cell lines in vivo, correlated with a concomitant reduction in their susceptibility to tumor-specific cytotoxic T lymphocytes (CTL) in vitro (Hui et al, 1991).…”

B7-1, IFNγ and anti-CTLA-4 co-operate to prevent T-cell tolerization during immunotherapy against a murine T-lymphoma

“…The BW-Sp3 cell line was derived from the original spontaneous BW5147 T cell lymphoma (AKR origin, Salk Institute, La Jolla, CA) by in vitro and in vivo passages, as described previously (Vanden Driessche T et al, 1994). The generation of BWSp3(IFN␥) and BWSp3(B7-1) cells was described earlier (Raes et al, 1995;Raes et al, 1998).…”