TUMOR-INDUCED MACROPHAGE TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION SUPPRESSES AUTOREACTIVE T-CELL PROLIFERATION

T cells can react to self-cells bearing the syngeneic major histocompatibility complex class II molecule Ia. Decreased autoreactive T cell responses are associated with cancer. Tumor growth causes syngeneic macrophages (MPHI) to suppress autoreactive T cell proliferation by decreasing MPHI Ia expression and increasing MPHI production of the suppressor molecule prostaglandin E2 (PGE2). Because MPHI produce tumor necrosis factor-alpha (TNF-alpha) during cancer, and TNF-alpha stimulates MPHI PGE2 synthesis, we determined if TNF-alpha mediates tumor-induced suppression of autoreactive T cell proliferation stimulated by syngeneic MPHI. We showed that tumor growth increases TNF-alpha production because tumor-bearing host (TBH) MPHI synthesized more TNF-alpha than normal host (NH) MPHI when cultured with lipopolysaccharide. Exogenous TNF-alpha increased NH CD4+ autoreactive T cell proliferation stimulated by syngeneic NH MPHI but not by TBH MPHI. When endogenous TNF-alpha activity was neutralized by anti-TNF-alpha antibody addition, T cell proliferation decreased when stimulated by NH MPHI but increased when stimulated by TBH MPHI. Kinetic studies showed that TNF-alpha affected MPHI-stimulated T cell proliferation during the first few hours (4 h) of the 96 h culture time. Indomethacin-treatment allowed TNF-alpha to increase T cell proliferation stimulated by TBH MPHI. A PGE2-specific enzyme-linked immunosorbent assay showed that TBH MPHI T cell cultures contained significantly more PGE2 than those containing NH MPHI, and that exogenous TNF-alpha increased PGE2 production in TBH MPHI cultures more than in NH MPHI cultures. Short-term (4 h) pretreatment of MPHI with TNF-alpha increased T cell proliferation stimulated by NH, but not TBH, MPHI. However, long-term (16 h) TNF-alpha pretreatment reversed TBH MPHI-mediated suppression, suggesting that early suppressor molecule production inhibits synthesis or activity of TNF-alpha-induced stimulatory monokines. Although TNF-alpha is known to increase T cell proliferation, these results show that the tumor-induced increase in MPHI TNF-alpha synthesis suppress autoreactive T cell proliferation, which is mediated by PGE2 production.