Nature review: IL-23 and autoimmunity

Cytokines are the chemical messengers of the immune system. They are secreted by a wide range of celltypes and bind to receptors on neighbouring cells, usually resulting in cellular activation or differentiation. This seemingly simple process is vital to the complex cellular machinery of the immune system, as it facilitates rapid communication between different immune cells, thus enabling the host to mount a fast and effective immune response to an invading pathogen. Specifically, the release of cytokines by cells in an infected area sends a chemical signal which activates and recruits other immune cells to the site of infection.

In recent years, the interleukin-17 (IL-17) family of cytokines have been of great interest to immunologists. This is because Th17 cells (T helper cells that produce IL-17) have been shown to be critical in the pathogenesis of autoimmunity. However, the actions of another cytokine, IL-23, are known to be necessary in order for Th17 cells to exert this pathogenic effect, although the precise mechanisms are not clear. A recent publication in Nature Immunology by McGeachy et al (1) has now shown that IL-23 is not simply maintaining the effects of Th17 cells, a commonly held hypothesis, but instead that the cytokine is necessary for the complete differentiation or 'fine-tuning' of activated T cells into effector Th17 cells. The authors accomplished these results by generating an IL-23-receptor (IL-23R) knockout mouse in which they observed a reduced susceptibility to experimental autoimmune encephalomyelitis (EAE).

They found that IL-23R-/- mice had similar levels of CD4+ T cells when compared to wildtype mice, but crucially there was far less infiltration of these cells into the CNS following the onset of EAE. In addition to the lack of infiltration, the cells in the IL-23R-/- mice produced less IL-17 than the same cells in the wildtypes (1). Thus, in the absence of the effects of IL-23 signaling, CD4+ T cells are impaired in their ability to both move to the necessary site of damage and secrete IL-17. This strongly suggested that the CD4+ T cells were not completely differentiating into Th17 cells in the IL-23R-/- mice.

Picture: IL-23-mediated differentiation of CD4+ T cells into Th17 cells

In addition, the authors show that IL-23-mediated differentiation of T cells into Th17 cells is time-dependent by measuring induction of Th17 cells in the draining lymph nodes in an adoptive cell transfer model. They found no difference between IL-23R-/- knockout and wildtype mice until day 6, when a significant lack of Th17 cells were observed in the draining lymph nodes in the knockout mice (1). Together these results suggest that in the absence of IL-23 signaling there are fewer Th17 cells in the circulation, and hence less infiltration into the CNS resulting in a decrease in the Th17-mediated pathogenic effects that contribute to the pathogenesis of EAE. The authors go on to show that IL-23 induces Th17 terminal differentiation by a mechanism which includes the phosphorylation of the transcription factor STAT3 (1).

This work is important as it reveals the importance of the role of IL-23 in Th17 cell development. This will open up new areas of research towards targeting IL-23 or possibly blocking the IL-23 receptor in an effort to inhibit the pathogenic effects of Th17 cells in autoimmunity. Indeed, an antibody directed towards the p40 subunit of IL-23 has already been shown to decrease inflammation in psoriatic patients, thus confirming the possible benefits of this novel approach.

(1) McGeachy et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009 Mar;10(3):314-24.