Deciphering the role of Th17 cells in human disease (original) (raw)
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Immunological Reviews, 2008
Our understanding of the role of T cells in human disease is undergoing revision as a result of the discovery of T-helper 17 (Th17) cells, a unique CD4 1 T-cell subset characterized by production of interleukin-17 (IL-17). IL-17 is a highly inflammatory cytokine with robust effects on stromal cells in many tissues. Recent data in humans and mice suggest that Th17 cells play an important role in the pathogenesis of a diverse group of immune-mediated diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma. Initial reports also propose a role for Th17 cells in tumorigenesis and transplant rejection. Important differences, as well as many similarities, are emerging when the biology of Th17 cells in the mouse is compared with corresponding phenomena in humans. As our understanding of human Th17 biology grows, the mechanisms underlying many diseases are becoming more apparent, resulting in a new appreciation for both previously known and more recently discovered cytokines, chemokines, and feedback mechanisms. Given the strong association between excessive Th17 activity and human disease, new therapeutic approaches targeting Th17 cells are highly promising, but the potential safety of such treatments may be limited by the role of these cells in normal host defenses against infection.
The role of Th17 cells in tumor immunity
Acta Haematologica Polonica, 2014
Since 1989 when Mosmann and Coffman showed that murine CD4+ T cells differentiate into two subsets of reciprocal patterns of cytokine secretion and function, defined as CD4+ T helper type 1 (Th1) and Th2, a great progress in understanding of Th cells and certain effector cytokines utilized by Th cells has been observed. This classic division was changed by the discovery of a new CD4+ helper T cells population which is characterized by the high expression of IL-17, named CD4+ T helper type 17 (Th17). More recently, the new Th subsets such as Th9 and Th22 cells, which play roles in the modulation of host immune responses, were discovered [1-3]. Th17 cell differentiation After the discovery of Th17 cells, many studies have been focused on the mechanisms that lead to the differentiation of CD4+ cells. At least several cytokines and their combinations, the presence of which determines the formation and a c t a h a e m a t o l o g i c a p o l o n i c a 4 5 (2 0 1 4) 1 5 5-1 6 0 a r t i c l e i n f o Article history:
Phenotypic and functional features of human Th17 cells
The Journal of …, 2007
T helper (Th) 17 cells represent a novel subset of CD4+ T cells that are protective against extracellular microbes, but are responsible for autoimmune disorders in mice. However, their properties in humans are only partially known. We demonstrate the presence of Th17 cells, some of ...
Blood, 2009
Th17 cells play an active role in autoimmune diseases. However, the nature of Th17 cells is poorly understood in cancer patients. We studied Th17 cells, the associated mechanisms, and clinical significance in 201 ovarian cancer patients. Tumor-infiltrating Th17 cells exhibit a polyfunctional effector T-cell phenotype, are positively associated with effector cells, and are negatively associated with tumor-infiltrating regulatory T cells. Tumor-associated macrophages promote Th17 cells through interleukin-1β (IL-1β), whereas tumor-infiltrating regulatory T cells inhibit Th17 cells through an adenosinergic pathway. Furthermore, through synergistic action between IL-17 and interferon-γ, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced dise...
Functional and phenotypic heterogeneity of Th17 cells in health and disease
European Journal of Clinical Investigation
Background: Th17 cells have nonredundant roles in maintaining immunity, particularly at mucosal surfaces. These roles are achieved principally through the production of cytokines and the recruitment of other immune cells to maintain the integrity of mucosal barriers and prevent the dissemination of microorganisms. Th17 cells are heterogeneous and exhibit a considerable degree of plasticity. This allows these cells to respond to changing environmental challenges. However, Th17 cells also play pro-inflammatory roles in chronic autoimmune diseases. The trigger(s) that initiate these Th17 responses in chronic autoimmune diseases remain unclear. Design: In this report, we provide an overview of studies involving animal models, patient data, genome wide association studies and clinical trials targeting IL-17 for treatment of patients to gain a better understanding of the pathogenic roles of Th17 cells play in a range of autoimmune diseases. Results: The report sheds light on likely triggers that initiate or perpetuate Th17 responses that promote chronic inflammation and autoimmunity. The divergent effects of tumour necrosis factor alpha blockade on Th17 cells in patients, is explored. Furthermore, we highlight the role of Th17 cells in inducing autoreactive B cells, leading to autoantibody production. Pathogenic bacterial species can change Th17 cell phenotype and responses. These findings provide insights into how Th17 cells could be induced to promoting autoimmune disease pathogenesis. Conclusion: This article provides an overview of the distinct roles Th17 cells play in maintaining immunity at mucosal surfaces and in skin mucosa and how their functional flexibility could be linked with chronic inflammation in autoimmune rheumatic diseases. 1 | INTRODUCTION Th17 cells are effector T cells characterized primarily by the production of IL-17, principally IL-17A and IL-17F but also IL-22, IL-21 and GM-CSF. 1 The cells play an important role in maintaining immunity, particularly at mucosal surfaces, but also contribute to chronic inflammation in autoimmune diseases. 1-3 Although many studies have explored the role of Th17 cells in the pathogenesis of autoimmune diseases using animal models, clinical samples from patients, clinical trials targeting IL-17 therapeutically and genome-wide association studies (GWAS), there is still a lack of understanding of how Th17 cells are transformed from nonpathogenic protective lymphocytes to a major Jonas Bystrom and Felix IL Clanchy have contributed equally.
Th17 cells: a new fate for differentiating helper T cells
Immunologic Research, 2008
Classically naïve CD4 + have been thought to diVerentiate into two possible lineages, T helper 1 (Th1) or T helper 2 (Th2) cells. Within this paradigm the pathogenesis of autoimmunity was suggested to predominantly relate to Th1 cells and the production of IFN-. However, there were many aspects of this model that did not seem to Wt, not the least of which was that IFN-was protective in some models of autoimmunity. During the past 2 years, remarkable progress has been made to characterize a new lineage of helper T cells. Designated Th17 cells, this lineage selectively produces proinXammatory cytokines including IL-17, IL-21, and IL-22. In the mouse, the diVerentiation of this new lineage is initiated by TGF -1 and IL-6 and IL-21, which activate Stat3 and induce the expression of the transcription factor retinoic acid-related orphan receptor (ROR t). IL-23, which also activates Stat3, apparently serves to maintain Th17 cells in vivo. In human cells, IL-1, IL-6, and IL-23 promote human Th17 diVerentiation, but TGF -1 is reportedly not needed. Emerging data have suggested that Th17 plays an essential role in the host defense against extracellular bacteria and fungi and in pathogenesis of autoimmune diseases. Selectively targeting the Th17 lineage may be beneWcial for the treatment of inXammatory and autoimmune diseases.
Harnessing the Therapeutic Potential of Th17 Cells
Mediators of Inflammation, 2015
Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of proand anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and ROR t while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon (IFN ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since ROR t is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases.
Arthritis Research & Therapy, 2008
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.