Role Of Th17 Cells Research Articles

Th17 cells and HIV infection.

This review summarizes the recent literature about the potential perturbation and role of Th17 cells in HIV pathogenesis. We discuss the recent findings on Th17 deficiency in HIV/simian immunodeficiency virus (SIV) infection and how this deficiency may impact the mucosal host defenses, potentially contributing to chronic immune activation. Th17 cells have been implicated in host defense against a variety of pathogens and are involved in the pathogenesis of autoimmune diseases. Recently, Th17 cells were shown to be perturbed during HIV infection in humans and SIV infection in nonhuman primates. Th17 cells were found to be infected in vitro by HIV and SIV and are significantly depleted in the gastrointestinal tract of HIV-infected individuals. In monkeys, Th17 cells are only depleted in the pathogenic SIV infection of rhesus macaques, which correlates with the progression to AIDS in these primates, whereas they remain intact in the nonpathogenic SIV infection of African green monkeys or sooty mangabeys. Th17 cells appear to be perturbed during HIV and SIV infection. This finding could have important implications in understanding the disruption of mucosal defenses in the gastrointestinal tract and potentially in predicting opportunistic infections during the course of HIV disease.

Th17 cytokines and arthritis

Th17 cells are implicated in human autoimmune diseases, such as rheumatoid arthritis (RA), although it has not been established whether this persistent destructive arthritis is driven by Th1 and/or Th17 cells. Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis as has been shown in several experimental arthritis models. Importantly, recent data from first clinical trials with anti-IL-17A antibody treatment in psoriatic arthritis patients and RA patients looks promising. This review summarizes the findings about the role of Th17 cells in arthritis and discusses the impact of the different Th17 cytokines in the pathogenesis of this disease. However, further studies are needed to unravel the interplay between IL-17A and other Th17 cytokines such as IL-17F, IL-22, and IL-21 in the pathoimmunological process of this crippling disease, in particular, whether regulating Th17 cell activity or specific combinations of Th17 cytokines will have additional value compared to neutralizing IL-17A activity alone. Moreover, tumor necrosis factor-positive Th17 cells are discussed as potential dangerous cells in driving persistent arthritis in human early RA.

Serum profile of Th17-related cytokines in patients with primary biliary cirrhosis

Objective:To observe the serum profile of Th17-related cytokines(IL-1β,IL-6,IL-17A,IL-23,and TGF-β)in patients with primary biliary cirrhosis,so as to study the role of Th17 cells in the pathogenesis of primary biliary cirrhosis(PBC).Methods:Seventy-eight patients with PBC,30 patients with HBV-related posthepatitic cirrhosis(PHC),and 60 healthy controls(HC)were enrolled in this study.The serum levels of above five Th17-related cytokines were determined by enzyme-linked immunosorbent assay(ELISA).Results:The levels of IL-1β,IL-6,IL-17A,and IL-23 in PBC group were significantly higher than those in HC group(P0.05);the levels of TGF-β were comparable between the PBC group and HC group.The levels of IL-1β,IL-6,and TGF-β were significantly lower and IL-17A,IL-23 were significantly higher in the PBC group compared with those in the PHC group(P0.05).Conclusion:Our findings indicate that PBC patients are in a status of chronic inflammation.Th17 subset may play an important role in the development and progression of PBC.

Costimulation of Th17 cells: adding fuel or putting out the fire in the inflamed gut?

Inflammatory bowel disease, typified by Crohn's disease and ulcerative colitis, is a common disorder characterized by recurrent and serious inflammation of the gastrointestinal tract. It is well documented that T cells play a pivotal role in the development of inflammatory bowel disease. Th17 cells are a unique T cell subpopulation implicated in inflammatory bowel disease and many other autoimmune/inflammatory diseases. However, the regulatory mechanism of Th17 activation and proliferation has not been defined completely. Recent studies have shown that the ligation of several costimulatory receptor-ligand pairs contributes to the activation, differentiation, and proliferation of T lymphocytes including the Th17 subset. In this review, we will discuss the emerging evidence on the role of Th17 cells in inflammatory bowel disease pathogenesis as well as the effect of costimulatory molecules on Th17 development and consider if the need for such costimulation of T lymphocytes provides a target for the development of novel therapeutic strategy.

Th17 cytokines and vaccine-induced immunity.

T helper type 17 (Th17) cells are a distinct lineage of T cells that produce the effector molecules IL-17, IL-17F, IL-21, and IL-22. Although the role of Th17 cells in primary immune responses against infections is well documented, there is growing evidence that the Th17 lineage maybe critical for vaccine-induced memory immune responses against infectious diseases. Here, we summarize recent progress in our understanding of the role of IL-17 in vaccine-induced immunity.

Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients

T helper 17 (Th17) cells and regulatory T (Treg) cells are two distinct subsets of CD4(+) T cells which have opposite effects on inflammation, autoimmunity and immunological rejection of foreign tissue. Treg cells have been shown to be important in maintaining materno-fetal tolerance, but the role of Th17 cells in human pregnancy and pathological pregnancy, especially in relation to unexplained recurrent spontaneous abortion (RSA), has not been investigated. In this study, we showed that the proportion of Th17 cells in the peripheral blood and decidua was significantly higher in unexplained RSA patients compared to normal, early pregnant women. Meanwhile, there was an inverse relationship between Th17 cells and Treg cells in the peripheral blood lymphocytes (PBL) and decidua in unexplained RSA. The expression of Th17 related factors, IL-17, IL-23 and retinoid orphan nuclear receptor (RORC), in PBL and decidua in unexplained RSA patients was significantly higher than normal, early pregnant women. This study is the first to define the occurrence of Th17 cells in unexplained RSA patients and in normal, early pregnant women. We suggest that these highly pro-inflammatory cells contribute to unexplained RSA, and the balance between Th17 cells and Treg cells may be critical to pregnancy outcomes.

Peripheral TH-17 Cells in Children with Allergic Rhinitis: Preliminary Report

Th17 is a subset of T helper lymphocytes and exerts pro-inflammatory activities. Recently, it has been reported that serum IL-17 levels are high in the most severe patients with birch allergy studied both outside and during the pollen season. This study aims to compare the frequency of peripheral IL-17-producing T cells in children with allergic rhinitis and in healthy controls. Ten children with allergic rhinitis and 5 healthy non-allergic subjects were evaluated. Th17 were evaluated by intracellular staining in ex-vivo T cell compartment. Ex- vivo PBMNC evaluation showed that allergic patients had higher frequencies of IL-17 producing T cells, both concerning CD4+ and CD8+ cells. In particular, there is a subset co-expressing IL-17 and IFN-gamma both for CD4+ and CD8+ cells. In conclusion, this preliminary study suggests a possible role of Th-17 cells in the response to allergens in children.

Th17 cells and human arthritic diseases

Th17 cells, though having been discovered just few years ago, is believed as the pathogenic T cells in many autoimmune diseases and chronic inflammatory diseases, such as rheumatoid arthritis (RA). Biologics targeting IL-17 have already been on clinical trial, and the results were recently reported. Although the importance of Th17 cells in animal models of arthritis is unquestionable, it is not recognized that there are only limited data on the role of Th17 cells and related cytokines in human arthritic diseases. In addition, the characteristics of human Th17 cells have not been fully defined, and there seem to be substantial differences between human and mouse Th17 cells. In this review, I will introduce and discuss about updated findings on human Th17 cells and its relation with human arthritic diseases.

Interleukin (IL)-23 mediates Toxoplasma gondii–induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17

Peroral infection with Toxoplasma gondii leads to the development of small intestinal inflammation dependent on Th1 cytokines. The role of Th17 cells in ileitis is unknown. We report interleukin (IL)-23–mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii–induced immunopathology. Moreover, IL-23–dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down-regulated and dispensable. CD4+ T cells were the main source of IL-22 in the small intestinal lamina propria. Thus, IL-23 regulates small intestinal inflammation via IL-22 but independent of IL-17. Gelatinases may be useful targets for treatment of intestinal inflammation.

Peripheral Th-17 cells in allergic rhinitis: New evidence

Background Th17 is a subset of T helper lymphocytes exerting inflammatory activities. Recently, it has been reported that serum IL-17 levels are high in patients with severe birch allergy. Aim of the study It was to compare the cytokine profile and the frequency of peripheral allergen-specific T helper producing IL-17 in patients with allergic rhinitis. Methods Twelve patients with persistent allergic rhinitis due to pollens and 5 healthy non-allergic subjects were evaluated during the pollen season. Th17 were evaluated by intracellular staining in T cell compartment ex-vivo and after short activation by allergens and control antigens. Results Ex-vivo PBMNC evaluation showed that allergic patients had higher frequencies of IL-17 producing T cells. Functional analysis after antigen-specific CD4+ T cell expansion demonstrated that allergic patients had higher frequencies of IL-17 producing T cells than normal subjects. Conclusion This preliminary study contributes to the knowledge concerning the possible role of Th-17 cells in the response to allergens.

TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn's disease

Tumor necrosis factor (TNF)-like protein 1A (TL1A) is a member of the TNF superfamily and contributes to the pathogenesis of Crohn's disease (CD) by stimulating T-helper (Th) 1 cells. In addition to Th1, recent studies have focused on the role of Th17 cells in the pathogenesis of CD. Here we tried to clarify the role of TL1A in Th1 and Th17 immunity in CD. TL1A expression was assessed by quantitative reverse-transcription polymerase chain reaction (RT-PCR) in lamina propria (LP) macrophages (LP-M phi s) from normal controls (NC) and patients with CD or ulcerative colitis (UC). Purified LP CD4(+) T cells were stimulated with TL1A and/or IL-23 and interferon gamma (IFN-gamma) and interleukin (IL)-17 levels were analyzed. We also examined the effect of TL1A on naïve CD4(+) T-cell differentiation. We found that LP-M phi s are a major producer of TL1A. TL1A expression was markedly enhanced in LP-M phi s from CD patients compared with NC or UC patients. IL-23, in addition to TL1A, was induced in LP-M phi s by commensal bacteria stimulation. TL1A and IL-23 synergistically promoted the production of IFN-gamma and IL-17 by LP T cells, while TL1A alone did not induce cytokine production. Furthermore, TL1A promoted Th17 differentiation from naïve T cells by LP-M phi s; however, IL-23 did not show any synergistic effects on Th17 differentiation. TL1A expressed in LP-M phi s might play an important role in the pathogenesis of CD by inducing Th1 and Th17 immunity. IL-23 differentially regulated these functions of TL1A on memory and naïve T cells.

Mechanisms of control of acute Friend virus infection by CD4+ T helper cells and their functional impairment by regulatory T cells

The role of cytotoxic CD8(+) T cells is well defined in retroviral immunity but the role of CD4(+) T helper (Th) cells is poorly understood. The Friend retrovirus (FV) murine infection model is a good model to study immune responses in retroviral infections and hence was used to characterize the role of Th cells during acute infection. In vivo depletion of Th cells in acutely infected mice demonstrated that Th cells were vital in controlling viral spread and onset of erythroleukaemia and for the maintenance of FV-specific CD8(+) T-cell and neutralizing antibody responses. Kinetic analysis of FV-specific Th-cell responses using class-II tetramers showed that the magnitude of the Th-cell response correlated with the level of resistance to FV-induced leukaemia in different mouse strains. FV-specific CD4(+) T-cell receptor beta-transgenic (TCRbeta-tg) T cells were adoptively transferred into mice infected for different time periods [1, 2 and 3 weeks post-infection (p.i.)] to investigate the direct antiviral effect of CD4(+) T cells in FV infection. Results indicated that FV-specific CD4(+) TCRbeta-tg T cells were functionally active until 2 weeks p.i., retaining their ability to produce gamma interferon (IFN-gamma) and reduce viral loads. However, the donor cells lost their antiviral activity starting from 3 weeks p.i. Interestingly, in vivo depletion of regulatory T cells (Tregs) at this time point restored IFN-gamma production by transferred CD4(+) T cells. The current study reveals that Th cells were critical for recovery from acute FV infection but were functionally impaired during the late phase of acute infection due to induced Tregs.

P3.27. Role of Th17 cells in head and neck cancer

P3.27. Role of Th17 cells in head and neck cancer

Introduction: The first Merinoff Symposium, ‘Systemic Lupus: Bringing Science to the Patient’

Introduction: The first Merinoff Symposium, ‘Systemic Lupus: Bringing Science to the Patient’

Breaking old paradigms: Th17 cells in autoimmune arthritis

Aberrant helper T cell activation has been implicated in the pathogenesis of an array of autoimmune diseases. In this review, we summarize evidence that suggests the involvement of a novel T cell subset, the Th17 lineage, in rheumatoid arthritis. In particular, we focus on the role of Th17 cells in inducing and perpetuating the chronic inflammation, cartilage damage, and bone erosion that are hallmark phases of joint destruction and consider current and emerging therapies that seek to disrupt the inflammatory Th17 network and shift the immune system back towards homeostasis.

The role of Th17 cells in adult patients with chronic idiopathic thrombocytopenic purpura

The role of Th17 cells in adult patients with chronic idiopathic thrombocytopenic purpura

IL-17 is required for protective immunity to nasal Brucella infections in an IFN-γ-dependent fashion (39.23)

Abstract Th1 and Th17 cells are the principal mediators of the inflammatory pathways. While the role of Th1 cells have been extensively studied for Brucella infections, there is little information on the function of IL-17 in response to Brucella infections. To evaluate such role, mice functionally deficient in IL-17 or IL-17 receptor (IL-17R-/-) mice were more susceptible to nasal Brucella infection than immunocompetent mice as evidenced by increased splenic weights and splenic CFUs. Interestingly, inhibition of IL-17 failed to enhance the IFN-γ response, but instead RT-PCR analysis revealed greater lung IL-13 mRNA transcripts than lungs from IL-17-sufficient mice. Splenic mononuclear cells from Brucella-infected mice depleted of IL-17 produced more IL-10, but less IFN-γ and IL-17 upon subsequent restimulation with heat-killed brucellae than the same cells from IL-17-sufficient mice. Interestingly, splenic mononuclear cells from infected IFN-γ-/- mice produced less IL-17, indicating that mice blocked in either IL-17 or IFN-γ pathways are impaired in their ability to produce either cytokine when infected with Brucella. These results implicate IL-17 is important for protection against nasal Brucella infections, and that IL-17 in combination with IFN-γ modulates the host immune responses to Brucella. This work is supported by USDA 2007-0612 and 2008-03776.

Correlating the phenotype of in vitro-polarized Th17 cells with expression of IL-17A and IL-17F (47.6)

Abstract The T-helper 17 (Th17) lineage has surfaced as a topic of great interest in the fields of inflammation and autoimmunity. The secretion of interleukin (IL)-17A and IL-17F has implicated these cells in many autoimmune diseases including rheumatoid arthritis, Crohn's disease, asthma and multiple sclerosis. IL-17A and IL-17F have been shown to form both homodimers and heterodimeric complexes. Characterization of the expression of these Th17 effector molecules together with surface proteins such as CCR6, CD161 and RORγt will be useful for studying further the role of Th17 cells in human disease. In this study, in vitro-polarized Th17 cells were analyzed for surface expression, secretion or intracellular expression of Th17-related proteins. Using an ELISA with minimal cross-reactivity to IL-17A/A and IL-17F/F, IL-17A/F was found to be a major product of in vitro-polarized Th17 cells. Furthermore, IL-17A/A expression was less than or equal to IL-17A/F, while IL-17F/F expression was consistently lower than IL-17A/A or IL-17A/F.

Increased Th17 cell activity in patients with early rheumatoid and psoriatic arthritis (137.30)

Abstract To gain insights into the role of Th17 cells in human autoimmune diseases, we analyzed Th17 cell biology in patients with ongoing inflammatory autoimmune arthritis (e.g., rheumatoid (RA) and psoriatic arthritis (PsA)), and for control in patients with osteoarthritis and healthy individuals. Frequencies of Th17 cells were significantly elevated in the blood of patients with early, treatment-naive RA and PsA. Moreover, upon activation in vitro, CD4 T cells from the patients yielded enhanced Th17 frequencies and elevated levels of IL-17. In contrast, Th1 frequencies and IFNγ production were not different between patients and controls. As the frequencies of Th17 cells and IL-17 production, but not of Th1 cells or IFNγ production correlated with disease activity, early inflammation in RA and PsA is characterized by both, selectively enhanced Th17 cell generation and increased Th17 cell activity. Of interest for the pathogenesis of autoimmune arthritis, CD4 T cells from early RA and PsA patients were partially resistant to the inhibitory capacity of IL-4 and IFNγ on Th17 generation, suggesting a potential mechanism underlying the breakdown of peripheral tolerance at disease onset. However, as effective immunosuppressive treatment was associated with normalization of Th17 cell activity in the patients, the data further suggest that Th17 cells might also contribute to sustained autoimmune inflammation in RA and PsA.

Inhibition of Th17 Cells Regulates Autoimmune Diabetes in NOD Mice

OBJECTIVEThe T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti–IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study.RESEARCH DESIGN AND METHODS AND RESULTSAlthough treatment with either anti–IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti–IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti–IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti–IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell–mediated dominant protective effect against autoimmunity.CONCLUSIONSThese studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease.