Abstract
The discovery in mice of a new lineage of CD4+ effector T helper (Th) cells that selectively produce IL-17 has provided exciting new insights into immune regulation, host defence, and the pathogenesis of autoimmune and other chronic inflammatory disorders. This population of CD4+ Th cells, which has been termed 'Th17', indeed plays an apparently critical role in the pathogenesis of some murine models of autoimmunity. Interestingly, murine Th17 cells share a common origin with Foxp3+ T regulatory cells, because both populations are produced in response to transforming growth factor-β, but they develop into Th17 cells only when IL-6 is simultaneously produced. Initial studies in humans have confirmed the existence of Th17 cells, but they have shown that the origin of these cells in humans differs from that in mice, with IL-1β and IL-23 being the major cytokines responsible for their development. Moreover, the presence in the circulation and in various tissues of Th cells that can produce both IL-17 and interferon-γ, as well as the flexibility of human Th17 clones to produce interferon-γ in addition to IL-17 in response to IL-12, suggests that there may be a developmental relationship between Th17 and Th1 cells, at least in humans. Resolving this issue has great implications in tems of establishing the respective pathogenic roles of Th1 and Th17 cells in autoimmune disorders. In contrast, it is unlikely that Th17 cells contribute to the pathogenesis of human allergic IgE-mediated disorders, because IL-4 and IL-25 (a powerful inducer of IL-4) are both potent inhibitors of Th17 cell development.
Highlights
The adaptive effector CD4+ T helper (Th)-mediated immune response is highly heterogeneous, based on the development of distinct subsets that are characterized by various profiles of cytokine production
Th1 and Th2 cells develop via activation of various transcription factors, the most important being signal transducer and activator of transcription (STAT)-4 and T box expressed in T cells (T-bet) for Th1 cells, and STAT-6 and GATA-binding protein (GATA)-3 for Th2 cells [5]
CIA = collagen-induced arthritis; dendritic cells (DCs) = dendritic cell; EAE = experimental autoimmune encephalomyelitis; GATA = GATA-binding protein; IFN = interferon; IL = interleukin; RA = rheumatoid arthritis; ROR = orphan retinoid nuclear receptor; STAT = signal transducer and activator of transcription; T-bet = T box expressed in T cells; TGF = transforming growth factor; Th = T helper; Treg = T regulatory
Summary
The adaptive effector CD4+ T helper (Th)-mediated immune response is highly heterogeneous, based on the development of distinct subsets that are characterized by various profiles of cytokine production. These data support the idea that IL-17 is involved in the pathogenesis of several autoimmune diseases in mice and possibly in humans In this context, the presence, and sometimes the prevalence, of Th1 cells in the inflammatory tissues of murine autoimmune disorders has been interpreted as a protective, rather than proinflammatory, mechanism, based on the following observations: IFN-γ or IFN-γ receptor deficient mice are still susceptible to EAE and CIA [45,46]; and IFN-γ inhibits development of Th17 cells [6]. All T cell clones specific for amoxicillin derived from this patient had a classic Th2 profile and none of them was able to produce IL-17 (unpublished data), supporting the view that Th17 cells do not play any role in uncomplicated, IgEmediated allergic disorders
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