The Immunobiology of Interleukin-35 and Its Regulation and Gene Expression

Interleukin-35 (IL-35) is the latest addition to the IL-12 family of heterodimeric cytokines, consisting of IL-12 p35 subunit and IL-27β subunit Epstein-Barr virus induced 3 (EBI3). Since its discovery, IL-35 has been shown to exhibit immunosuppressive activities which are distinct from other members of IL-12 family. IL-35 is also unique in that it is expressed primarily by regulatory T-cells (T_regs) rather than by antigen-presenting cells (APCs). IL-35 can directly suppress effector T-cell proliferation and function and inhibit the differentiation of Th17 cells. It is also able to expand regulatory responses to promote tolerance to infections by generating a potent population of IL-35-producing inducible Tregs (iTr35). As the new cellular sources of IL-35 such as CD8⁺T_regs, B_regs, and tolerogenic dendritic cells DCs (tolDCs) are identified, more immunoregulatory functions of this cytokine are explored. IL-35 has been shown to be associated with a range of autoimmune diseases and cancer models. It appears to be a promising diagnostic biomarker. A greater understanding of the expression and regulatory mechanisms of IL-35 will be beneficial to the development of novel immune therapies.