17 and 23
Authors: Sally Hamour, Alan D. Salama
Journal: Journal of the American Society of Nephrology (2009)

The discovery of the cytokine IL-17 more than 10 yr ago1 paved the way for the recent identification of a distinct subset of helper T cells producing IL-17 (Th17 cells). This novel proinflammatory class of Th cells2 disrupts the Th1/Th2 paradigm that had shaped our view of the immune system and immune-mediated disease for more than 20 yr.3 Th1 cells, regulated by the transcription factor T-bet and characterized by the production of IFN-γ and IL-12, provide defense against viruses and intracellular pathogens and are associated with autoimmunity, whereas Th2 cells, modulated by GATA-3 and producing IL-4 and IL-13, provide immunity against extracellular parasites and play a role in the promotion of allergy. The novel Th17 cells represent a third distinct lineage of helper CD4+ T cells that are regulated by a specific transcription factor, RoR-γt,4 and produce IL-17. IL-17 possesses pleiotropic effects,5 including release of proinflammatory cytokines (TNF-α, IL-6, and IL-8), upregulation of adhesion and MHC molecules, and recruitment of monocytes and neutrophils. Th17 cells in mice develop from naive CD4+ cells in the presence of TGF-β and IL-6; however, in humans, unraveling their pathway to differentiation is more complex. Initially, Th17 differentiation was thought to be driven by IL-1 and enhanced by IL-6 and IL-23.6,7 More recently, TGF-β and IL-21 also seem integral for their differentiation in humans.8 Significantly, IL-23 is a cytokine important in both terminal differentiation and maintenance of Th17 cells. The discovery that IL-23 is a heterodimer, sharing a structural p40 subunit with IL-12 and expressing a unique p19 subunit,9 prompts a reexamination of experimental work, using IL-12p40 gene-targeted mice and neutralizing antibodies to p40, that suggested a primary role for IL-12–producing Th1 cells inthe pathogenesis of autoimmune disease. In certain models, such as experimental autoimmune encephalomyelitis9–11 and collagen-induced arthritis,12,13 disease is significantly ameliorated in IL-17–or IL-23–deficient mice, even in the presence of IL-12, demonstrating that pathology is mediated by Th17 cells induced by IL-23. Importantly, the generation of Th17 cells and the regulatory foxp3-expressing T regulatory cells (Tregs), which mediate tolerance to self-antigens, seem mutually exclusive.14 Thus, induction of Th17 cells not only results in a proinflammatory effector population but also deters Treg generation, potentially promoting autoimmunity through two pathways. Although many autoimmune models are dependent on IL-17, this is not true for all (diabetes in the NOD mouse, for example, is dependent on IFN-γ15), and, until now, no data were available relating to renal disease. It is therefore timely that, in this issue of JASN, two groups independently present evidence for the role of Th17 cells in two mouse models of glomerulonephritis, using IL-17–and IL-23–deficient mice.16,17 Paust et al.17 demonstrate in mouse mesangial cells that proinflammatory IL-17 upregulates CCL2, CCL3, and CCL20, which contribute to recruitment of T cells and monocytes. Then, by inducing nephrotoxic nephritis in IL-17−/− and IL-23p19−/− null mice, they show animals deficient in IL-17 or IL-23 are protected from nephritis with less T cell and monocyte recruitment compared with wild-type, with less albuminuria, fewer crescents, better preserved renal function, but with similar humoral responses. IL-23p19−/− mice have fewer Th17 cells, in keeping with the role of IL-23 in maintaining the Th17 population. Overall, in nephritic wild-type animals, 3 to 7% of renal CD3+ T cells produced IL-17 compared with only 1% in IL-23p19−/− mice. In a complementary study, Ooi et al.16 use a model of experimental autoimmune glomerulonephritis induced by immunization with α3(IV)NCI, the Goodpasture antigen, in a series of null animals to dissect out the contribution of IL-23 and IL-17 cytokines in disease. This group has previously shown that IL-12p40−/− animals are protected but that IFNγ−/− animals developed more severe disease. In this study, using IL-12p35−/− (IL-12 deficient, IL-23 intact), IL-12p40−/− (IL-12 and IL-23 deficient), and IL-23p19−/− (IL-23 deficient, IL-12 intact) mice, they show that deficiency of IL-23 is necessary and sufficient to protect from disease regardless of IL-12 status and, furthermore, that protection is not mediated by a reciprocal increase in foxP3 Tregs. IL-23–deficient animals demonstrate attenuated cellular and humoral immunity, less renal disease, and fewer regulatory cells. Although IL-23–deficient animals expressed less IL-17, as would be expected, they also express less IFN-γ, IL-4, TNF, and monocyte chemoattractant protein 1, leading the authors to conclude that IL-23 deficiency additionally leads to a nonselective deficit in T cell cytokine production and a more general effect on immune responses, a finding not seen in IL-23–deficient animals in other organ models of autoimmune disease. Hence, it seems in models of experimental glomerulonephritis that Th17 lineage cells and IL-23 and IL-17 cytokines are critically important. There also are interesting differences between the models with respect to the immunologic modulations induced by IL-23 deficiency, but, overall, both show a significantly attenuated cellular immune response. Of course unanswered questions remain. If only 3 to 7% of renal CD3+ T cells produce IL-17 in immune complex nephritis, then what is the role of the other 93% of renal T cells? Only 4 to 20% produce IFN-γ, so what is the cytokine profile of the remaining cells? How does IL-23 exert its far-reaching effects on immune responses beyond modulating IL-17 in the anti–glomerular basement membrane model, and why does it differ from other organ models of autoimmunity? Why is there no increase in the number of Tregs in IL-23 deficiency when a reciprocal pathway for development with Th17 cells has been described? How do these findings in susceptible mice relate to patients? The pleiotropic proinflammatory functions of IL-17 make it an attractive candidate as a key mediator of glomerulonephritis and systemic autoimmune disease. IL-17 in humans is detected in the synovium of patients with rheumatoid arthritis and the serum of those with systemic lupus erythematosus. IL-17 is also overexpressed in inflammatory airway diseases, transplant rejection, psoriasis, multiple sclerosis, inflammatory bowel disease, and systemic sclerosis. Proving causality, however, is more difficult. Although autoimmune disease in inbred mice can show significant immune polarization, in humans, there is often a more mixed phenotype. Indeed, in humans, T cells secreting both IL-17 and IFN-γ18 and, more recently, IL-17–producing Tregs that express both RoR-γt and foxp3 have been isolated19; therefore, the key questions are how well these experimental models of murine glomerulonephritis, demonstrating a key role for Th17 cells, truly replicate human disease and what role these cells play in patients with immune-mediated kidney disease. Finally, to make these prime numbers really matter to the renal community, the benefits of modulating IL-17 or IL-23 as a novel therapeutic approach need demonstration. DISCLOSURES None. We are grateful to Charles Pusey for helpful comments and for support from the National Institute for Health Research Biomedical Research Centre Funding Scheme.