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

T cells can react to self-cells bearing the syngeneic major histocompa tibility complex class II molecule Ia. Decreased autoreactive T cell r esponses are associated with cancer. Tumor growth causes syngeneic mac rophages (MPHI) to suppress autoreactive T cell proliferation by decre asing MPHI Ia expression and increasing MPHI production of the suppres sor molecule prostaglandin E2 (PGE2). Because MPHI produce tumor necro sis factor-alpha (TNF-alpha) during cancer, and TNF-alpha stimulates M PHI PGE2 synthesis, we determined if TNF-alpha mediates tumor-induced suppression of autoreactive T cell proliferation stimulated by syngene ic MPHI. We showed that tumor growth increases TNF-alpha production be cause tumor-bearing host (TBH) MPHI synthesized more TNF-alpha than no rmal host (NH) MPHI when cultured with lipopolysaccharide. Exogenous T NF-alpha increased NH CD4+ autoreactive T cell proliferation stimulate d by syngeneic NH MPHI but not by TBH MPHI. When endogenous TNF-alpha activity was neutralized by anti-TNF-alpha antibody addition, T cell p roliferation decreased when stimulated by NH MPHI but increased when s timulated 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 culture s more than in NH MPHI cultures. Short-term (4 h) pretreatment of MPHI with TNF-alpha increased T cell proliferation stimulated by NH, but n ot TBH, MPHI. However, long-term (16 h) TNF-alpha pretreatment reverse d TBH MPHI-mediated suppression, suggesting that early suppressor mole cule production inhibits synthesis or activity of TNF-alpha-induced st imulatory monokines. Although TNF-alpha is known to increase T cell pr oliferation, these results show that the tumor-induced increase in MPH I TNF-alpha synthesis suppress autoreactive T cell proliferation, whic h is mediated by PGE2 production.