Interleukin-10 in the Control of Tumor Immunity and Autoimmunity.

Abstract

IL-10 is known as an immunosuppressive cytokine. However, we have identified an immune-stimulatory role of IL-10 in tumor immunity. Interestingly, the incidence of chemically-induced tumors, transplanted tumor growth, and lung foci are increased in IL-10-deficient (IL-10-/-) mice. This phenomenon is associated with increased myeloid-derived suppressor cells (MDSCs) and CD4+Foxp3+ regulatory T(reg) cells, along with decreased natural killer (NK) cells, CD8+ T cells and T cell effector cytokines in the IL-10-/- tumor microenvironment. IL-10-/- MDSCs express high levels of interleukin IL-1 and MHC, and efficiently induce Treg cells. Genetic and biological blockade of the IL-1 signaling pathway reduces tumor growth and partially rescues effector T cell tumor infiltration and function, and decreases tumor angiogenesis and Treg cell tumor infiltration. This indicates that endogenous IL-10 may stimulate tumor immunity through direct activation of effector T cells, suppression of MDSCs and MDSC-induced Tregs, and reduction of pro-tumor activity mediated by inflammatory cytokines. Thus, our data challenge the dogma that IL-10 is solely immune suppressive. The mechanistic link between IL-10 and Th17 cells in autoimmune disease remains poorly understood. We have therefore examined the relationship of IL-10 to Th17 cells in both mouse and human autoimmune models. IL-10-/- mice are susceptible to development of chronic enterocolitis. We have observed spontaneous systemic increases in Th17 cells in IL-10-/- mice. IL-10-/- dendritic cells (DC) produce more IL-1 than IL-10+/+ counterparts and are more powerful inducers of Th17 cells; this effect is abrogated upon IL-1 receptor (IL-1R) blockade. In vivo abrogation of IL-1 signaling reduces Th17 levels in IL-10-/- mice. Similar to IL-10-/- mice, Crohn’s disease patients have elevated numbers of Th17 cells, and ex vivo production of IL-17 by these cells is inhibited upon anti-IL-1R treatment. Stimulated DCs from Crohn’s patients produce high levels of IL-1. In intestinal mucosa, IL-10 levels were inversely proportional to those of IL-1 and IL-17, suggesting a similar mechanism of control of Th17 cells in human pathology. IL-10 thus constrains Th17 cell development through repression of IL-1, and in turn tempers autoimmune responses. Taken together, our data expands upon the known IL-10 biology in immune regulation of antitumor immunity and autoimmunity.