PROMOTION OF MACROPHAGE-STIMULATED AUTOREACTIVE T-CELL PROLIFERATION BY INTERLEUKIN-10 - COUNTERACTION OF MACROPHAGE SUPPRESSOR ACTIVITY DURING TUMOR-GROWTH

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 E(2) (PGE(2)) 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 PGE(2); 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 bn 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 turner 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.