Differentiation and function of Th17 T cells (original) (raw)
Related papers
International Immunology, 2008
T helper 17 (T h 17) cells represent a new subset of CD41 effector T cells which have been described in both mice and humans. However, some differences seem to exist between murine and human T h 17 cells with regard to their features, origin and role in immunopathology. Murine T h 17 cells share their developmental origin with Foxp31 Treg cells, indeed naive T-cell precursors can be differentiated to regulatory T (Treg) cells by transforming growth factor-b (TGF-b) alone, whereas the contemporaneous presence of TGF-b and IL-6 gives origin to T h 17 cells. Human T h 17 cells which consistently express the CC chemokine receptor 6 and the equivalent of the murine NK1.1, CD161, appear to exclusively originate in response to IL-1b and IL-23 from a small subset of CD1611CD41 T-cell precursors detectable in the thymus and in umbilical cord blood. These cells constitutively express the T h 17-driving transcription factor retinoic acid-related orphan receptor (ROR)gt and the IL-23R and can also give origin to T h 1 cells or T h 2 cells under the appropriate polarizing conditions. By contrast, human CD161-naive T cells only give rise to T h 1 and T h 2 cells, but not T h 17 cells. TGF-b may not exert a direct critical role in human T h 17 cell differentiation, but indirectly favours their development by inhibiting the development of T h 1 cells, which are much more susceptible than T h 17 cells to its suppressive activity on cell proliferation. Moreover, while murine T h 17 are pathogenic in some murine models of autoimmunity where T h 1 cells seem to play a protective role, both T h 17 and T h 1 certainly contribute to the pathogenesis of human autoimmune and other chronic inflammatory disorders.
The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases
Archivum Immunologiae et Therapiae Experimentalis, 2015
The end of twentieth century has introduced some changes into T helper (Th) cells division. The identification of the new subpopulation of T helper cells producing IL-17 modified model of Th1-Th2 paradigm and it was named Th17. High abilities to stimulate acute and chronic inflammation made these cells ideal candidate for crucial player in development of autoimmune disorders. Numerous publications based on animal and human models confirmed their pivotal role in pathogenesis of human systemic and organ-specific autoimmune diseases. These findings made Th17 cells and pathways regulating their development and function a good target for therapy. Therapies based on inhibition of Th17-dependent pathways are associated with clinical benefits, but on the other hand are frequently inducing adverse effects. In this review, we attempt to summarize researches focused on the importance of Th17 cells in development of human autoimmune diseases as well as effectiveness of targeting IL-17 and its pathways in pre-clinical and clinical studies.
Th17 cells in inflammatory conditions
The review of diabetic studies : RDS, 2006
CD4(+) T cells have been subdivided into different subsets, largely on the basis of the cytokines they produce. These subsets include Th1, Th2 and regulatory T cells. Recently, another population of T cells have been described, namely Th17, which are characterized by their production of IL-17. Two other important cytokines, which are related to each other, are associated with the development of Th cells, namely IL-12 and IL-23. While IL-12 plays a key role in the differentiation of naïve T cells to Th1 cells, IL-23 promotes the expansion of Th17 cells. IL-12 and IL-23 are heterodimers with a shared subunit, p40. They furthermore bind to receptors which have unique and shared subunits. Several previous studies have evaluated the role of IL-12 in inflammatory diseases on the basis of p40. Therefore a reevaluation of the role of IL-12 and Th1 cells in a range of inflammatory conditions has been carried out. This new wave of studies has resulted in the recognition of the role of IL-23 a...
Th17 T cells: Linking innate and adaptive immunity
Seminars in Immunology, 2007
While the cytokine IL-17 has been cloned and described more than 10 years ago [Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 1995;3(6):811-21; Kennedy J, Rossi DL, Zurawski SM, Vega Jr F, Kastelein RA, Wagner JL, et al. Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR + CD4-CD8-T cells. J Interferon Cytokine Res 1996;16(8):611-7], it was only 2 years ago that IL-17 producing T cells have been classified as a new distinct CD4 T cell subset [Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, 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 2005;6(11):1123-32] and only in 2006 the molecular mechanisms underlying their differentiation were identified [Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24(2):179-89; Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441(7090):235-8; Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006;441(7090):231-4].
Role of TH-17 Cells in Rheumatic and Other Autoimmune Diseases
Rheumatology : Current Research, 2011
In humans multiple pathways can induce TH-17 cell differentiation, whereas in mice this process is mostly modulated by IL-6 and TGF-β. IL-17 produced by TH-17 cells has been associated with a number of inflammatory autoimmune diseases including psoriasis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. In this review, we have primarily focused on the role of TH-17 cells/IL-17 in the pathogenesis of rheumatoid arthritis and experimental arthritis. The potential role of TH-17 cells in rheumatoid arthritis progression has been demonstrated by correlating the percent TH-17 cells or levels of IL-17 with rheumatoid arthritis disease activity score and C-reactive protein levels. Further, previous studies suggest that IL-17 mediated vascularization may lay the foundation for rheumatoid arthritis joint neutrophil and monocyte recruitment as well as cartilage and bone destruction. The profound role of IL-17 in the pathogenesis of experimental arthritis may be due to its synergistic effect with TNF-α and IL-1β. Although the initial clinical trial employing anti-IL-17 antibody has been promising for rheumatoid arthritis, future studies in humans will shed more light on how anti-IL-17 therapy affects rheumatoid arthritis and other autoimmune disease pathogenesis.
Nature, 2006
On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T H ) cells are traditionally thought to differentiate into T H 1 and T H 2 cell subsets. T H 1 cells are necessary to clear intracellular pathogens and T H 2 cells are important for clearing extracellular organisms 1,2 . Recently, a subset of interleukin (IL)-17-producing T (T H 17) cells distinct from T H 1 or T H 2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury 3-5 . In contrast, CD4 1 CD25 1 Foxp3 1 regulatory T (T reg ) cells inhibit autoimmunity and protect against tissue injury 6 . Transforming growth factor-b (TGF-b) is a critical differentiation factor for the generation of T reg cells 7 . Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation 8,9 , completely inhibits the generation of Foxp3 1 T reg cells induced by TGF-b. We also demonstrate that IL-23 is not the differentiation factor for the generation of T H 17 cells. Instead, IL-6 and TGF-b together induce the differentiation of pathogenic T H 17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T H 17) T cells that induce autoimmunity and regulatory (Foxp3 1 ) T cells that inhibit autoimmune tissue injury.
Nature Immunology, 2008
Interleukin 17 (IL-17)-producing T helper 17 cells (T(H)-17 cells) have been described as a T helper cell subset distinct from T helper type 1 (T(H)1) and T(H)2 cells, with specific functions in antimicrobial defense and autoimmunity. The factors driving human T(H)-17 differentiation remain controversial. Using a systematic approach combining experimental and computational methods, we show here that transforming growth factor-beta, interleukin 23 (IL-23) and proinflammatory cytokines (IL-1beta and IL-6) were all essential for human T(H)-17 differentiation. However, individual T(H)-17 cell-derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global T(H)-17 cytokine profile, were differentially modulated by T(H)-17-promoting cytokines. Transforming growth factor-beta was critical, and its absence induced a shift from a T(H)-17 profile to a T(H)1-like profile. Our results shed new light on the regulation of human T(H)-17 differentiation and provide a framework for the global analysis of T helper responses.
IL-17 and the Th17 lineage in systemic lupus erythematosus
Current Opinion in Rheumatology, 2008
Revising the Th1/Th2 paradigm: Th17 cells and their signature cytokines For over 20 years, the dominant paradigm in T-cellmediated disease, whether infectious or autoimmune, stated that immune responses are controlled by Th1 or Th2 cells [1 ]. Th1 cells secrete interferon gamma (IFNg) and are induced to differentiate by cues from IL-12, whereas Th2 cells secrete IL-4, IL-5 and IL-13 and are triggered to develop by IL-4. Development of each T-helper lineage is self-reinforcing and mutually antagonistic, and all diseases have traditionally been viewed in the confines of this model. A major revolution in T-cell biology occurred with the discovery of a new subset of CD4 þ T cells, termed 'Th17' after their signature cytokine, IL-17 [2,3 ]. The implications for understanding-and ultimately treatingautoimmunity are profound. For years, it was considered that Th1 cells were the major mediators of inflammation in autoimmune syndromes, particularly in rheumatoid arthritis (RA), Crohn's disease and multiple sclerosis, but it is now evident that Th17 cells are the primary drivers of these autoimmune diseases. This discovery emerged from reports comparing IL-12 and IL-23, het-erodimeric cytokines that share a common subunit, 'IL-12p40'. Mice with a targeted deletion in IL-12p40 are resistant to many autoimmune diseases. However, in many instances, IFNgÀ/À mice do not phenocopy IL-12p40 mice, but rather show unchanged or enhanced susceptibility to disease [1 ]. When mice lacking the unique IL-12p35 subunit of IL-12 were created, they failed to induce Th1 cells as expected, but remained susceptible to induction of mouse models of RA and multiple sclerosis [4,5]. Conversely, mice deficient in the IL-23-specific subunit p19 still developed Th1 cells, but were resistant to autoimmune disease [6,7]. Additional studies implicating IL-23 came from the observation that this cytokine could stimulate T cells to secrete IL-17 in vitro [8]. Two reports in 2005 demonstrated convincingly that the Th17 cell population arises independently of Th1 and Th2, as the key cytokines and transcription factors involved in differentiating classic T-helper subsets were dispensable for Th17 development [9,10]. Moreover, Th1 and Th2 cells suppress Th17, explaining in part why this lineage was overlooked. Although these early studies presumed that IL-23 was the inductive cytokine for the Th17 lineage, a flurry of reports demonstrated
Development and function of TH17 cells in health and disease
Journal of Allergy and Clinical Immunology, 2009
T H 17 cells are the newest member of the T H cell family and are characterized by their ability to produce specific cytokines such as IL-17, IL-22, IL-17F, and CCL20. In this review, conditions for the differentiation of T H 17 cells are defined in both murine and human systems, with discussion of T H 17-specific cytokines and transcription factors. Functionally, T H 17 cells contribute to host defense as a new effector T H cell subset with a role in protection against extracellular bacteria through activities on immune and nonimmune cells. Their activities, however, are also pivotal in the development of autoimmune diseases under pathologic conditions. T H 17 cells are also beginning to be associated with the development and pathophysiology of allergic diseases, such as allergic contact dermatitis, atopic dermatitis, and asthma. Lymphoid tissue inducer-like cells and natural killer-like cells, termed RORgt 1 NKp46 1 or NK-22 cells, might also play a role in allergic diseases because of their propensity to