Immunology of IL-12: An update on functional activities and implications for disease

Abstract

As its first identified member, Interleukin-12 (IL-12) named a whole family of cytokines. In response to pathogens, the heterodimeric protein, consisting of the two subunits p35 and p40, is secreted by phagocytic cells. Binding of IL-12 to the IL-12 receptor (IL-12R) on T and natural killer (NK) cells leads to signaling via signal transducer and activator of transcription 4 (STAT4) and subsequent interferon gamma (IFN-γ) production and secretion. Signaling downstream of IFN-γ includes activation of T-box transcription factor TBX21 (Tbet) and induces pro-inflammatory functions of T helper 1 (T_H1) cells, thereby linking innate and adaptive immune responses. Initial views on the role of IL-12 and clinical efforts to translate them into therapeutic approaches had to be re-interpreted following the discovery of other members of the IL-12 family, such as IL-23, sharing a subunit with IL-12. However, the importance of IL-12 with regard to immune processes in the context of infection and (auto-) inflammation is still beyond doubt. In this review, we will provide an update on functional activities of IL-12 and their implications for disease. We will begin with a summary on structure and function of the cytokine itself as well as its receptor and outline the signal transduction and the transcriptional regulation of IL-12 secretion. In the second part of the review, we will depict the involvement of IL-12 in immune-mediated diseases and relevant experimental disease models, while also providing an outlook on potential translational approaches.

Keywords: IL-12; STAT4; TH1 cells; cytokines; immunology; ustekinumab.

Figure 1. The IL-12 family. Schematic representation of IL-12 family members, their associated receptors and corresponding subunits

Figure 2. Secretion and signaling of IL-12. Antigen-presenting cells (APCs) like dendritic cells sense PAMPs (pathogen-associated molecular patterns) through toll like receptors (TLRs). Subsequently, several transcription factors are activated to induce the transcription of IL-12p35 and IL-12p40 (for more details confer text). The secreted IL-12 heterodimer binds to its receptor on NK and T cells, recruits the tyrosine kinases JAK2 and TYK2 and activates JAK2 by tyrosine phosphorylation. Activated JAK2 phosphorylates the IL12Rβ2 subunit, which in turn activates STAT4 via phosphorylation. Subsequently, phosphorylated STAT4 homo- or heterodimerizes, enabling translocation to the nucleus, where it regulates gene transcription by binding to target DNA. A main target gene is IFN-γ, which in turn induces transcriptional activation of IL-12 production via IRF-1 and ICSBP.

Figure 3. Role of IL-12 in T_H1 differentiation. Naïve T cells exposed to IL-27 express the IL-12 receptor heterodimer, sensitizing the cells for the influence of IL-12, which - together with IFN-γ from NK cells and feedback loops, IFN-α and IFN-β induces upregulation of the transcription factor Tbet and downregulation of GATA3 leading to a preliminary T_H1 commitment. Further exposure to IL-12 leads to the upregulation of STAT4 in these early T_H1 cells, followed by their differentiation into T_H1 effector and memory T cells. IL-18 and IL-23 contribute to the fixation, amplification and maintenance of the T_H1 cell effector functions. Differentiated T_H1 cells produce IFN-γ to enhance Tbet expression via STAT1, thus closing a positive feedback loop. Further, they are able to promote IL-10 secreting Tr1 cells, a process probably mediated by IL-12 and IL-27 signaling.