INTERLEUKIN-4 IS EFFECTIVE IN RESTORING CYTOTOXIC T-CELL ACTIVITY THAT DECLINES DURING IN-VIVO PROGRESSION OF A MURINE B-LYMPHOMA

We previously reported [Chakrabarti et al. (1992) Cell Immunol 142:54; 144:455] that, in a murine B lymphoma model 2C3, idiotype (Id)-specif ic CD8(+) cytotoxic T lymphocytes (CTL) are generated in mice followin g hyperimmunization with irradiated tumor cells, and that they are eff ective in tumor rejection. The present study reveals that 2C3-specific CTL are also induced in spleens during tumor progression, but are not sustained. At the early stage of tumor growth, the splenic T cells fo llowing a 5-day incubation in vitro with killed 2C3 tumor targets, pro duce high levels of cytokines, namely interleukin-4 (IL-4), IL-10 and interferon gamma (IFN gamma). Their cytotoxic T lymphocyte (CTL) activ ity and cytokine levels, except IL-2, sharply decline at the late stag e when the mice are increasingly moribund. Although the decline in cyt okine level is also evident with CD4(+) T cells, a precipitous and con current decrease occurs primarily in the IL-4 level with both CD4(+) a nd CD8(+) T cells of late-tumor-bearing animals (TBA). Study with the unseparated splenocytes also reveals that sevenfold less IL-4 is produ ced at the late stage. Furthermore, the cytotoxicity of CTL from late TBA can be effectively restored by addition of supernatants from the s plenocyte culture of early TBA, or by IL-4, but not by IFN gamma and I L-10. In addition, only IL-4-activated CD8(+) T cells from the late TB A are found, by Winn assay, to be protective in vivo. Thus it appears that IL-4, required to sustain antitumor CTL activity, is consumed by T and possibly other cells at the late stage of tumor growth, thereby compromising host immunity against the tumor. We contend that inductio n or maintenance of protective immunity depends not only on the tumor antigen but also on the specific cytokine milieu in a tumor-bearing ho st.