T helper-17 cells, which are involved in immune responses, arise from a pool of precursor cells. It emerges that their differentiation is partly mediated by the IL-21 protein, which originates from the helper cells themselves.
Over the past 500 million years, vertebrates have evolved an elegant solution to the lifelong challenge posed by microbes: adaptive immunity. The adaptive immune response is triggered when a foreign, or non-self, molecule (an antigen) is encountered. This process is partly controlled by several types of T cell, each of which arises from a shared pool of precursor cells that have not previously encountered an antigen. So mechanisms must be in place to enforce the commitment of each 'naive' T cell to differentiate along one of the lineages.
For their part, the long-recognized T helper type 1 (TH1) and type 2 (TH2) lineages produce immune mediator proteins called cytokines that advance the development of one lineage to the exclusion of the other. Certain TH1 and TH2 cytokines act in an autocrine manner — that is, once produced, they bind to cell-surface receptors on new, naive T cells, thereby activating their own signalling pathways. These cytokines also suppress the development of the recently identified proinflammatory cells of the TH17 lineage. However, no cytokines from TH17 cells that would promote TH17 development had been identified. Three reports — by Nurieva et al.1 and Korn et al.2 on pages 480 and 484 of this issue, and by Zhou et al. in Nature Immunology3 — now fill this gap by identifying the interleukin (IL)-21 protein as the TH17-secreted autocrine cytokine.
TH17 cells produce cytokines such as IL-17A and IL-17F, which regulate immune responses specially adapted to clearing extracellular bacteria and fungi. Interest in TH17 cells has been intense — not just because their discovery shored up a deficiency in our understanding of the arsenal of adaptive responses to microbial pathogens, but also because these cells have been implicated in the pathogenesis of several chronic inflammatory diseases, including inflammatory bowel disease, psoriasis and rheumatoid arthritis4.
In an immune response, specialized cells called dendritic cells recruit antigen-naive helper T-cell precursors. Dendritic cells not only process and present microbial antigens to the antigen receptor on the precursor T cells, but they also produce, or elicit the production of, cytokines that guide the differentiation of these cells. The resultant effector T cells then specifically eradicate the microbial invader initially presented by the dendritic cells.
Differentiation of TH17 cells is triggered by a pair of cytokines — transforming growth factor (TGF)-β and IL-6 — which induce the expression of an orphan nuclear receptor known as retinoic acid receptor-related orphan receptor (ROR)-γ (refs 5, 6, 7, 8). This gene transcription factor prepares TH17 cells to respond to IL-23, a third cytokine that had already been associated with TH17 differentiation9.
Unlike TH1 and TH2 cells, TH17 cells had not been found to produce cytokines that reinforce their own differentiation, apparently being unable to beget their own kind through an autocrine mechanism. The three new papers1,2,3 rectify this misconception, showing that IL-21, whose expression is induced in developing TH17 cells by dendritic-cell-derived IL-6, could sustain and amplify TH17-cell differentiation through an autocrine feedback loop, bypassing any further requirement for IL-6.
In addition to promoting TH17-cell differentiation, TGF-β promotes the differentiation of a subset of T cells known as induced regulatory T (Treg) cells. In contrast to effector T cells, Treg cells are responsible for maintaining immune tolerance: they limit responses mediated by effector T cells that could injure host tissues. To shift TGF-β-induced Treg development towards TH17 requires IL-6. So Korn et al.2 predicted that, in IL-6-deficient mice, both the development of TH17 cells and the induction of a mouse model of multiple sclerosis would be impaired, instead favouring Treg development. This proved to be the case. However, when the authors depleted IL-6-deficient mice of Treg cells, the development of TH17 effector cells was partially restored, indicating an IL-6-independent pathway to TH17 differentiation. By screening for cytokines that might substitute for the effect of IL-6, they identified IL-21.
In complementary studies, Nurieva et al.1 and Zhou and colleagues3 compared the total gene expression of T helper cells that had differentiated under different conditions. Both teams found that, under conditions known to promote TH17-cell development, levels of messenger RNA for IL-21 were enhanced, indicating induction of its encoding gene. These groups1,3 also found that IL-21 was as effective in inducing the expression of ROR-γ and the receptor for IL-23 as was IL-6. But, compared with IL-6-deficient T cells, cells deficient in IL-21 were profoundly impaired in inducing IL-23 receptor, ROR-γ and IL-17 in response to IL-6. Thus, IL-21, not IL-6, seems to be the main inducer of the IL-23 receptor.
Could IL-21 induce its own expression through a ROR-γ-independent pathway? Possibly; ROR-γ-deficient T cells expressed normal levels of IL-21, but expressed reduced levels of IL-17A, IL-17F and IL-22 (refs 1, 3). This indicates that, in the molecular-signalling pathway, IL-21 induction is upstream of, and independent of, ROR-γ.
Together, these studies support a revised model of TH17-cell development. Thus, IL-21 is both necessary and sufficient for the differentiation of TH17 cells, acting downstream of IL-6 and upstream of ROR-γ to promote the expression of the IL-23 receptor. This, in turn, prepares cells for IL-23-mediated completion of TH17-cell differentiation (Fig. 1).
It was known that IL-21 suppresses the production of another cytokine, IFN-γ, both by cytolytic T cells, which destroy infected cells, and by TH1 cells10. It is therefore plausible that, in promoting the development of TH17 cells, another function of IL-21 is to suppress IFN-γ, which can potently inhibit TH17-cell differentiation.
The possibility that IL-21 is an essential inductive and maintenance factor for TH17-mediated immune responses raises the prospect that it will be a target for therapeutic intervention, either to curb the pathogenic (autoimmune) effects of TH17 or to enhance its protective (anti-pathogen) effects.
Nurieva, R. et al. Nature 448, 480–483 (2007).
Korn, T. et al. Nature 448, 484–487 (2007).
Zhou, L. et al. Nature Immunol. doi:10.1038/ni1488 (2007).
Weaver, C. T. et al. Annu. Rev. Immunol. 25, 821–852 (2007).
Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. Immunity 24, 179–189 (2006).
Mangan, P. R. et al. Nature 441, 231–234 (2006).
Bettelli, E. et al. Nature 441, 235–238 (2006).
Ivanov, I. I. et al. Cell 126, 1121–1133 (2006).
Murphy, C. A. et al. J. Exp. Med. 198, 1951–1957 (2003).
Mehta, D. S., Wurster, A. L. & Grusby, M. J. Immunol. Rev. 202, 84–95 (2004).
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