In the classic model of immune system response, naive effector T cells differentiate into two kinds of cells that combat antigens. T helper type 1 (TH1) cells clear intracellular pathogens, while T helper type 2 (TH2) cells control certain parasitic infections. In 2005, Casey Weaver's team at the University of Alabama at Birmingham identified a third class of T helper cell that produces the cytokine interleukin 17 (IL-17) in response to autoimmune tissue injury, which they named TH17 cells.
Weaver's team was trying to explore the relationship between TH1 and IL-17; IL-17 had been identified years earlier, but its exact role in immune signaling was unclear. By blocking interferon-γ (IFN-γ) - a...
The results of this first Hot Paper were quickly picked up by immunologists and developed into a new field of research on the third T helper cell lineage. In the other Hot Papers highlighted here, researchers identified some of the factors contributing to TH17 signaling. Their findings contributed to a basic understanding of T cell lineage suppression. The complete signaling pathway to TH17 is still obscure, however, and researchers continue to interrogate potential players.
Finding a different path
Brigitta Stockinger's group at the Medical Research Council's Division of Molecular Immunology in London looked for the reason that IL-17 is secreted from activated T cells. Before the presence of a novel TH1-independent pathway was established, previous work had shown that the cytokine IL-23 was linked to IL-17 expression, but not sufficiently to induce differentiation of TH17 cells from naive T cells. Instead, they checked out the proinflammatory cytokine IL-6 and the immunosuppressive cytokine TGF-β, which together have been shown to suppress the two other T helper cell lineages. The Stockinger team found that, in addition to IL-23, the combination of TGF-β and IL-6 was essential for TH17 differentiation.
In the second Hot Paper, Weaver's group found that when TGF-β was added to primary cultures with neutralized IL-4 (a cytokine also associated with suppressing the TH2 pathway) and IFN-γ, they found strong induction of IL-17-producing cells, strengthening the vital role of TGF-β in the pathway.
The whole picture of findings suggested that the successful signaling of TH17 required cooperation between TGF-β and the cytokine IL-6, while suppressing both TH1 and TH2 pathways. Indeed, mutually exclusive immune responses and T cell differentiations evolved, very likely, to ensure that the correct immune response arises in a self-regulated manner, and the immune response isn't a chaotic system of defense, says Weaver. This accounts for the reason that all three lineages of T helper cells act on themselves in a positive-feedback loop, while suppressing expression of other signaling pathways.
The new players
Subsequent research has shed considerable light on the signaling pathway required for TH17 differentiation. In part, it revealed that downstream of cytokine signaling, the nuclear receptor RORγt is required for the differentiation of the lineage.
Charles Drake's team at Johns Hopkins University showed in vivo that the transcription factor STAT3 is required for generating TH17 responses in several immune models, including pneumonitis.
The ability of the body to recognize and mitigate tumor growth may be linked to the IL-17 pathway. A paper last year in Nature showed that IL-23 and IL-17 together are increased in human cancers, and that mice predisposed to tumor development had reduced incidence of tumor growth with enhanced expression of IL-23.
References1. L.E. Harrington et al., "Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages," Nat Immunol, 6:1123-32, 2005. (Cited in 220 papers) 2. M. Veldhoen et al., "TGF-b in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells," Immunity, 24:179-89, 2006. 3. P.R. Mangan et al., "Transforming growth factor-b induces development of the TH17 lineage," Nature, 441:231-4, 2006. (Cited in 163 papers) 4. E. Bettelli et al., "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells," Nature, 441:235-8, 2006. (Cited in 236 papers) 5. I.I. Ivanov et al., "The orphan nuclear receptor RORgt directs the differentiation program of proinflammatory IL-17+ T helper cells," Cell, 126:1121-33, 2006. 6. T.J. Harris et al., "An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity," J Immunol, 179:4313-7, 2007. 7. J.S. Stumhofer et al., "Interleukins 27 and 6 induce STAT3 mediated T cell production of interleukin 10," Nature Immunol, published online November 11, 2007. 8. J.L. Langowski et al., "IL-23 promotes tumour incidence and growth," Nature, 442:461-5, 2006.
Data derived from the Science Watch/Hot Papers database and the Web of Science (Thomson ISI) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age.L.E. Harrington et al., "Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages," Nat Immunol, 6:1123-32, 2005. (Cited in 220 papers) P.R. Mangan et al., "Transforming growth factor-β induces development of the TH17 lineage," Nature, 441:231-4, 2006. (Cited in 163 papers) E. Bettelli et al., "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells," Nature, 441:235-8, 2006. (Cited in 236 papers)