Trends in Immunology
Understanding the IL-23–IL-17 immune pathway
Introduction
Interleukin (IL)-23 is a novel member of the IL-12 heterodimeric cytokine family. Because it shares the common p40 subunit and IL-12Rβ-1 receptor with IL-12, IL-23 was predicted to have a similar role to IL-12 in promoting T helper (Th)1-type responses. However, it is becoming increasingly evident that IL-23 has unique roles in regulating immunity. Whereas IL-12 drives the classical Th1 response characterized by interferon (IFN)γ production, IL-23 drives a T cell population that is characterized by the production of the IL-17-related cytokines IL-17A and IL-17F 1, 2 (Table 1). As a result of the prominent production of IL-17, we refer here to these T cells as Th17 cells. Recent studies have suggested that these cells have a dominant role in provoking chronic autoimmune inflammation of the central nervous system (CNS) and joints 2, 3, 4. The observation that IL-12 and IFNγ can suppress Th17 function has provided an explanation for the increased autoimmunity observed in animals deficient in IL-12p35, IL-12Rβ2, IFNγ or Signal transducer and activator of transcription 1 (STAT1) 3, 4, 5, 6, 7. Yet, other Th1 signaling components, such as STAT4 and T-bet, are required for autoimmune pathogenesis 5, 8, suggesting that these factors have a broader role in addition to activating Th1 cells. Are T-bet and STAT4 signaling also required for Th17 development? What transcription factors drive the Th17 immune pathway? Are there differential triggers for the production of IL-12 and IL-23, and what roles do these two immune pathways have in host defense? Here, by analyzing how these pathways are activated after the host receives a danger signal, we speculate on the range of responses set in motion by this newly discovered immune pathway.
Section snippets
Differential regulation of IL-12 and IL-23 production
Antigen-presenting dendritic cells (DCs) and macrophages produce IL-12 and IL-23 in response to environmental danger signals. Given the unique roles of these cytokines, mechanisms must exist to regulate their differential expression. Many toll-like receptor agonists, including lipopolysaccharide, CpG and PolyI:C have been shown to enhance the expression of the cytokine subunits p40, p35 and p19, resulting in the release of bioactive IL-12 and IL-23 9, 10, 11, 12, 13, 14, 15. The production of
IL-23 promotes the development of a novel T helper subset that is distinct from the classical Th1 and Th2 lineages
The original concept that Th cells can be divided into two distinct lineages based on their cytokine secretion profile and functional properties was proposed by Mosmann et al. [25] nearly 20 years ago. Th1 cells are important for cell-mediated immunity and Th2 cells are associated with humoral responses. At that time, Mosmann and Coffman [26] predicted that ‘…further divisions of helper T cells may have to be recognized before a complete picture of helper T cell function can be obtained’. The
Lineage origin of Th1 and Th17 cells
What is the lineage relationship between Th1 and Th17 cells? Over the past 15 years, the Th1 developmental pathway has been the subject of intense investigation. There is general agreement that IL-12 activation of STAT4 is necessary for optimal differentiation of naïve T cells into IFNγ-producing Th1 cells. IFNγ then activates the STAT1 transcription factor and subsequent T-bet expression. T-bet activation is required for optimal IL-12R-β2 expression and IL-12 responsiveness in Th1 cells 5, 31,
Evolutionary significance of the IL-23–IL-17 immune axis
If the price for a dysregulated IL-23–IL-17 immune axis is immunopathology and autoimmune inflammation, there must be strong evolutionary pressures to conserve this immune pathway. What benefit does IL-23 provide to the host? In addition to driving Th17 development, thereby promoting chronic inflammatory responses, recent observations suggest that another function of IL-23 might be closely associated with the influx of neutrophils during acute infections. IL-23 is produced by sentinel dendritic
Local tissue inflammatory response
In view of the proposed evolutionary significance of IL-23, one might predict that the IL-23 immune response would have a vital role in peripheral tissues such as the skin, gastrointestinal tract and lung. Indeed, there is mounting evidence that IL-23, expressed early in response to danger signals, has an important role in driving early local immune responses. For example, in the skin, IL-23 and IL-17 can be found in psoriatic lesions as a possible result of bacterial stimulation 30, 38. It is
Conclusions
The discovery of a novel immune pathway that is important for chronic inflammation and autoimmune inflammation has dramatically changed our view of cell-mediated immune responses. Whereas previously, the protective effects of a Th1 response always seemed to be interconnected to the risk of developing immune pathology, discovery of the IL-23–IL-17 pathway has revealed that the cellular immune response is a much more fine-tuned process. The acute response to danger signals received in the lung,
Update
Two newly published papers 53, 54 provided critical data supporting the hypothesis that IL-17 producing T cells are indeed a novel T helper subset.
Acknowledgements
We thank Robert Coffman, Tim Mosmann and John Curnutte for helpful discussions in the preparation of this article.
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