Cytokine regulation of immune tolerance

The immune system provides defenses against invading pathogens while maintaining immune tolerance to self-antigens. This immune homeostasis is harmonized by the direct interactions between immune cells and the cytokine environment in which immune cells develop and function. Herein, we discuss three non-redundant paradigms by which cytokines maintain or break immune tolerance. We firstly describe how anti-inflammatory cytokines exert direct inhibitory effects on immune cells to enforce immune tolerance, followed by discussing other cytokines that maintain immune tolerance through inducing CD4+Foxp3+ regulatory T cells (Tregs), which negatively control immune cells. Interleukin (IL)-2 is the most potent cytokine in promoting the development and survival of Tregs, thereby mediating immune tolerance. IL-35 is mainly produced by Tregs, but its biology function remains to be defined. Finally, we discuss the actions of proinflammatory cytokines that breach immune tolerance and induce autoimmunity, which include IL-7, IL-12, IL-21, and IL-23. Recent genetic studies have revealed the role of these cytokines (or their cognate receptors) in susceptibility to autoimmune diseases. Taken together, we highlight in this review the cytokine regulation of immune tolerance, which will help in further understanding of human diseases that are caused by dysregulated immune system.