Promotion of Macrophage-Stimulated Autoreactive T Cell Proliferation by Interleukin-10: Counteraction of Macrophage Suppressor Activity During Tumor Growth

• Published in: Immunobiology (1979) Vol. 192; no. 3; pp. 155 - 171
• Main Authors: Alleva, David G., Elgert, Klaus D.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier GmbH 01.02.1995
• Subjects: Animals; Autoantigens - pharmacology; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Dinoprostone - biosynthesis; Down-Regulation; Interleukin-10 - immunology; Interleukin-10 - physiology; Lymphocyte Activation - immunology; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness - immunology; Neoplasm Invasiveness - pathology; Nitrites - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Up-Regulation; NO; IL; PGE 2; MHC; ATCC; LPS; IFN-γ; TNF-α; MΦ; 3H-TdR; NH; SEM; TBH; ELISA
• ISSN: 0171-2985; 1878-3279
• DOI: 10.1016/S0171-2985(11)80094-X

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 (MΦ). Tumor-bearing hosts (TBH) have decreased autoreactivity partly because tumors increase MΦ secretion of suppressor molecules like prostaglandin E 2 (PGE 2) and decrease MΦ MHC class II expression. Because interleukin (IL)-10, a cytokine produced by T cells, MΦ, and tumor cells, inhibits production of most MΦ suppressor molecules, we determined if IL-10 could reverse tumor-induced murine splenic MΦ-mediated suppression of autoreactive T cell proliferation. Tumor growth enhanced activated MΦ production of PGE 2, nitric oxide, and tumor necrosis factor-α (TNF-α). IL-10 strongly reduced or inhibited MΦ production of these molecules. When added to pure normal host (NH) CD4 + T cells, NH syngeneic splenic MΦ stimulated autoreactive T cell proliferation more than did TBH splenic MΦ. Exogenous IL-10 or MΦ preincubation with IL-10 restored TBH MΦ-stimulated autoreactivity to normal levels. IL-10 treatment had little or no effect on NH MΦ-stimulated autoreactivity. IL-10 inhibited TBH MΦ secretion of suppressor molecules in T cell proliferation assays because supernatants from IL-10-pretreated TBH MΦ-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 MΦ was slightly, but significantly decreased. Although IL-10 is known to inhibit MΦ foreign antigen-presenting cell-dependent T cell proliferation, this study shows that IL-10 restores autoreactive T cell functions during tumor growth by counteracting MΦ production of inhibitory molecules. These data suggest that IL-10 up-regulates anti-cancer autoreactive T cell responses by down-regulating suppressor MΦ activity.