Tumour growth causes suppression of autoreactive T-cell proliferation by disrupting macrophage responsiveness to interferon-gamma.
Normal immune homeostasis is regulated partly by a small population of CD4+ T cells that react to autologous major histocompatibility complex class-II molecules on self-cells. Decreased autoreactive T-cell responses are associated with cancer. Tumour growth causes syngeneic macrophages (M phi) to suppress autoreactive T-cell proliferation by decreasing M phi class-II expression and increasing M phi production of the suppressor molecule prostaglandin E2 (PGE2). Because interferon-gamma (IFN-gamma) is a potent M phi activation molecule which regulates both M phi PGE2 and class-II expression, the effects of IFN-gamma on tumour-induced suppression of autoreactive T-cell proliferation were investigated. Exogenous IFN-gamma increased normal host (NH) CD4+ autoreactive T-cell proliferation stimulated by syngeneic NH M phi but decreased proliferation stimulated by tumour-bearing host (TBH) M phi. Antibody (Ab) neutralization of endogenous IFN-gamma activity reduced TBH M phi-mediated suppression. Kinetic studies showed that endogenous IFN-gamma suppressor activity was not exclusive during T-cell activation. Indomethacin treatment blocked IFN-gamma-induced suppression in TBH M phi-T cell cultures. TBH M phi-T cell cultures contained significantly more PGE2 than those containing NH M phi. Exogenous IFN-gamma increased early PGE2 production in TBH M phi cultures but decreased production in NH M phi cultures. The Ab-mediated neutralization of endogenous transforming growth factor-beta or tumour necrosis factor-alpha reduced TBH M phi-mediated suppression and blocked IFN-gamma-induced suppression. Short-term treatment of M phi with IFN-gamma before their addition to T cells caused TBH M phi to stimulate T-cell proliferation, which suggests that early suppressor molecule production by TBH M phi inhibits synthesis or activity of IFN-gamma-induced stimulatory monokines. These results show that tumour growth causes M phi to suppress autoreactive T-cell responses by allowing IFN-gamma to induce M phi suppressor molecules, which block production or activity of stimulatory monokines.
Alleva
D G
DG
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406.
Burger
C J
CJ
Elgert
K D
KD
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000276:immunology; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000276:immunology*; D011994:Recombinant Proteins; D013154:Spleen / Q000276:immunology
D011994:Recombinant Proteins; D008748:Methylcholanthrene; D007371:Interferon-gamma; D015232:Dinoprostone