Gradual Loss of T-Helper 1 Populations in Spleen of Mice During Progressive Tumor Growth

BACKGROUND: The carefully orchestrated events that result in a protective immune response are coordinated to a large extent by cytokines produced by T helper 1 (Th1) and T helper 2 (Th2) T-cell subsets, which are two arms of the immune system. Th1 cells preferentially produce interleukin 2 (IL-2), interferon gamma (IFN gamma), and tumor necrosis factor (TNF), resulting in a cellular response that helps to eliminate infected cells. In contrast, Th2 cells produce IL-4, IL-5, IL-6, and IL-10 and stimulate an antibody response that helps to prevent the cells from becoming infected. The clinical progression of several infectious diseases, including human immunodeficiency virus, some types of parasitoses, and tuberculosis, is thought to be associated with the predominance of a Th2-type T-cell response. Recent reports have demonstrated the presence of T cells producing Th2 lymphokines (IL-4, IL-6, and IL-10) in tumor-infiltrating lymphocytes of renal cell carcinoma. PURPOSE: The purpose of this study was to investigate at the molecular level whether there was any change in the splenic T cells of mice with progressively growing tumors from a Th1 to a Th2 DNA-binding pattern or phenotype. METHODS: Splenic T cells from mice bearing renal cell carcinoma or MCA-38 colon carcinoma were tested for cytokine production after in vitro activation. Nuclear extracts of splenic T cells were used for the DNA-binding assay using IFN-gamma core promoter region, the kappa B (kappa B) site from immunoglobulin gene, and the nuclear factor of activated T-cell (NFAT) site from IL-2 gene. RESULTS: Splenic T cells from mice bearing renal cell carcinoma or MCA-38 colon carcinoma preferentially produced Th2 cytokines (i.e., IL-4) upon activation and showed a marked decrease in Th1 cytokine (particularly IFN gamma) production compared with the production observed in normal splenic T cells. The DNA-binding assay with the IFN-gamma core promoter region confirmed the gradual decline in the nuclear transcription factors associated with the Th1 phenotype during tumor progression in both tumor models. Renal cell carcinoma-bearing mice, successfully treated with flavone-8-acetic acid and recombinant human IL-2, showed a reversion to a Th1-like pattern. In addition, nuclear extracts of T cells from tumor-bearing animals showed a Th2-type kappa B-binding pattern. Moreover, the NFAT complex present in the normal splenic T cells was lost at the later stages of tumor progression; instead, a new complex was present in mice bearing long-term tumors. CONCLUSION: T cells from tumor-bearing mice lose the Th1 phenotype with progressive tumor growth.