title: Promotion of macrophage-stimulated autoreactive T cell proliferation by interleukin-10: counteraction of macrophage suppressor activity during tumor growth.
abstract: CD4+ autoreactive T cells are a major cell population in regulating immune responses to altered autologous neoplastic cells. Normal autoreactive T cells recognize major histocompatibility complex (MHC) class II molecules in association with self-peptides on antigen-presenting cells, such as macrophages (M phi). Tumor-bearing hosts (TBH) have decreased autoreactivity partly because tumors increase M phi secretion of suppressor molecules like prostaglandin E2 (PGE2) and decrease M phi MHC class II expression. Because interleukin (IL)-10, a cytokine produced by T cells, M phi, and tumor cells, inhibits production of most M phi suppressor molecules, we determined if IL-10 could reverse tumor-induced murine splenic M phi-mediated suppression of autoreactive T cell proliferation. Tumor growth enhanced activated M phi production of PGE2, nitric oxide, and tumor necrosis factor-alpha (TNF-alpha). IL-10 strongly reduced or inhibited M phi production of these molecules. When added to pure normal host (NH) CD4+ T cells, NH syngeneic splenic M phi stimulated autoreactive T cell proliferation more than did TBH splenic M phi. Exogenous IL-10 or M phi preincubation with IL-10 restored TBH M phi-stimulated autoreactivity to normal levels. IL-10 treatment had little or no effect on NH M phi-stimulated autoreactivity. IL-10 inhibited TBH M phi secretion of suppressor molecules in T cell proliferation assays because supernatants from IL-10-pretreated TBH M phi-syngeneic NH T cell cultures had decreased levels of suppressor molecules. When endogenous IL-10 activity was neutralized with anti-IL-10 monoclonal antibody, autoreactive T cell proliferation stimulated by NH or TBH M phi was slightly, but significantly decreased. Although IL-10 is known to inhibit M phi foreign antigen-presenting cell-dependent T cell proliferation, this study shows that IL-10 restores autoreactive T cell functions during tumor growth by counteracting M phi production of inhibitory molecules. These data suggest that IL-10 up-regulates anti-cancer autoreactive T cell responses by down-regulating suppressor M phi activity.
authors.affiliation: Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Alleva
authors.forename: K D
authors.initials: KD
authors.lastname: Elgert
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D015536:Down-Regulation; D016753:Interleukin-10 / Q000276:immunology* / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000276:immunology / Q000473:pathology; D009573:Nitrites / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D001324:Autoantigens; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015232:Dinoprostone