Th17细胞和Treg细胞的细胞因子调节网络

Th17细胞和Treg细胞是CD4+T细胞的新亚群,在分化发育、功能发挥的过程中受到Th1型、Th2型效应细胞以及自身分泌产生细胞因子的调节,参与自身免疫病、感染、肿瘤等疾病的发生发展。通过对Th17和Treg分化发育、和功能发挥过程中的关键调节因子进行阻断或加强,可以上调或下调Th17和Treg在疾病中的表达,以用于疾病的预防和诊治。     

Human Th17 cells

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.     

Increased number of Tc17 and correlation with Th17 cells in patients with immune thrombocytopenia

Background

IL-17-secreting CD8+ T cells (Tc17 subset) have recently been defined as a subpopulation of effector T cells implicated in the pathogenesis of autoimmune diseases. The role of Tc17 and correlation with Th17 cells in the pathophysiology of immune thrombocytopenia (ITP) remain unsettled.

Design and Methods

We studied 47 ITP patients (20 newly-diagnosed and 27 with complete response) and 34 healthy controls. IL-17-producing CD3+CD8+ cells (Tc17) and IL-17-producing CD3+CD8− cells (Th17) were evaluated by flow cytometry and expressed as a percentage of the total number of CD3+ cells. Specific anti-platelet glycoprotein (GP) GPIIb/IIIa and/or GPIb/IX autoantibodies were measured by modified monoclonal antibody specific immobilization of platelet antigens. Peripheral blood mononuclear cells of ITP patients were isolated, incubated in the presence of 0, 0.25, 0.5, or 1 µmol/L of dexamethasone for 72 h, and collected to detect Tc17 and Th17 cells by flow cytometric analysis.

Results

IL-17 was expressed on CD3+CD8− and CD3+CD8+ T cells. The percentages of Tc17 and Th17 cells in newly-diagnosed patients were significantly elevated compared to controls, and Tc17 was decreased after clinical treatment. The Th17∶Tc17 ratio was significantly lower in newly-diagnosed patients compared with controls, and was increased in patients who had complete response. There was a significantly positive correlation between Tc17 and Th17 cells in the control group, but not in the ITP patients. A positive correlation existed between Tc17 and the CD8∶CD4 ratio, as well as CD8+ cells in patients with ITP. The frequencies of Tc17 were marginally higher in autoantibody-negative patients than autoantibody-positive patients. Moreover, both Tc17 and Th17 cell percentages decreased as the concentration of dexamethasone in the culture media increased in ITP patients.

Conclusions

Tc17 and the Th17 subset are involved in the immunopathology of ITP. Blocking the abnormally increased number of Tc17 may be a reasonable therapeutic strategy for ITP.     

Trypanosomiasis-induced Th17-like immune responses in carp

Background

In mammalian vertebrates, the cytokine interleukin (IL)-12 consists of a heterodimer between p35 and p40 subunits whereas interleukin-23 is formed by a heterodimer between p19 and p40 subunits. During an immune response, the balance between IL-12 and IL-23 can depend on the nature of the pathogen associated molecular pattern (PAMP) recognized by, for example TLR2, leading to a preferential production of IL-23. IL-23 production promotes a Th17-mediated immune response characterized by the production of IL-17A/F and several chemokines, important for neutrophil recruitment and activation. For the cold blooded vertebrate common carp, only the IL-12 subunits have been described so far.

Methodology/Principal Findings

Common carp is the natural host of two protozoan parasites: Trypanoplasma borreli and Trypanosoma carassii. We found that these parasites negatively affect p35 and p40a gene expression in carp. Transfection studies of HEK293 and carp macrophages show that T. carassii-derived PAMPs are agonists of carp TLR2, promoting p19 and p40c gene expression. The two protozoan parasites induce different immune responses as assessed by gene expression and histological studies. During T. carassii infections, in particular, we observed a propensity to induce p19 and p40c gene expression, suggestive of the formation of IL-23. Infections with T. borreli and T. carassii lead to an increase of IFN-γ2 gene expression whereas IL-17A/F2 gene expression was only observed during T. carasssii infections. The moderate increase in the number of splenic macrophages during T. borreli infection contrasts the marked increase in the number of splenic neutrophilic granulocytes during T. carassii infection, along with an increased gene expression of metalloproteinase-9 and chemokines.

Conclusion/Significance

This is the first study that provides evidence for a Th17-like immune response in fish in response to infection with a protozoan parasite.     

IL-17 and Th17 cells in tuberculosis

Tuberculosis is primarily a disease of the lung. Constant expression of cellular immunity in this organ is required to control Mycobacterium tuberculosis growth, but this can also result in chronic inflammation and pathologic consequences. During primary tuberculosis both IFN-γ and IL-17 are induced: both are potent inflammatory cytokines capable of inducing expression of chemokines that promote cell recruitment and granuloma organization throughout infection. During the chronic phase, a balance between Th1 and Th17 responses needs to be achieved to control bacterial growth and limit immunopathology, as a shift of the response towards excessive IL-17 production may sustain extensive neutrophil recruitment and tissue damage. Thus, regulation of Th1 and Th17 responses during tuberculosis is essential to promote anti-mycobacterial immunity and prevent extensive immunopathological consequences.     

Glutamine metabolism in Th17/Treg cell fate: applications in Th17 cell-associated diseases

Alteration in the Th17/Treg cell balance is implicated in various autoimmune diseases and these disease-associated pathologies.Increasing investigations have shown that glutamine metabolism regulates the differentiation of Th17 and Treg cells. Here we summarize the mechanisms by which glutamine metabolism regulates Th17/Treg cell fate. Some examples of a glutamine metabolism-dependent modulation of the development and progression of several Th17/Treg cell-associated diseases are provided afterward. This review will provide a comprehensive understanding of the importance of glutamine metabolism in the fate of Th17/Treg cell differentiation.     

Th1 and Th17 cells regulate innate immune responses and bacterial clearance during central nervous system infection

Brain abscesses arise following parenchymal infection with pyogenic bacteria and are typified by inflammation and edema, which frequently results in a multitude of long-term health problems. The impact of adaptive immunity in shaping continued innate responses during late-stage brain abscess formation is not known but is important, because robust innate immunity is required for effective bacterial clearance. To address this issue, brain abscesses were induced in TCR αβ knockout (KO) mice, because CD4(+) and NKT cells represented the most numerous T cell infiltrates. TCR αβ KO mice exhibited impaired bacterial clearance during later stages of infection, which was associated with alterations in neutrophil and macrophage recruitment, as well as perturbations in cytokine/chemokine expression. Adoptive transfer of either Th1 or Th17 cells into TCR αβ KO mice restored bacterial burdens and innate immune cell infiltrates to levels detected in wild-type animals. Interestingly, adoptively transferred Th17 cells demonstrated plasticity within the CNS compartment and induced distinct cytokine secretion profiles in abscess-associated microglia and macrophages compared with Th1 transfer. Collectively, these studies identified an amplification loop for Th1 and Th17 cells in shaping established innate responses during CNS infection to maximize bacterial clearance and differentially regulate microglial and macrophage secretory profiles.     

Th17 and Th22 cells in psoriatic arthritis and psoriasis

Introduction

The aim of this study was to characterize interleukin 17 (IL-17) and interleukin 22 (IL-22) producing cells in peripheral blood (PB), skin, synovial fluid (SF) and synovial tissue (ST) in patients with psoriasis (Ps) and psoriatic arthritis (PsA).

Methods

Flow cytometry was used to enumerate cells making IL-22 and IL-17, in skin and/or SF and PB from 11 patients with Ps and 12 patients with PsA; skin and PB of 15 healthy controls and SF from rheumatoid arthritis (RA) patients were used as controls. Expression of the interleukin 23 receptor (IL-23R) and chemokine receptors CCR4 and CCR6 was examined. Secretion of IL-17 and IL-22 was measured by ELISA. ST was analysed by immunohistochemical staining of IL-17 and IL-22.

Results

Increased frequencies of IL-17+ and IL-22+ CD4+ T cells were seen in PB of patients with PsA and Ps. IL-17 secretion was significantly elevated in both PsA and Ps, whilst IL-22 secretion was higher in PsA compared to Ps and healthy controls. A higher proportion of the CD4+ cells making IL-17 or IL-22 expressed IL-23R and frequencies of IL-17+, CCR6+ and CCR4+ T cells were elevated in patients with Ps and those with PsA. In patients with PsA, CCR6+ and IL-23R + T cells numbers were elevated in SF compared to PB. Increased frequencies of IL-17+ and IL-22+ CD4+ T cells were demonstrated in Ps skin lesions. In contrast, whilst elevated frequencies of CD4+ IL-17+ cells were seen in PsA SF compared to PB, frequencies of CD4+ IL-22+ T cells were lower. Whereas IL-17 expression was equivalent in PsA, osteoarthritis (OA) and RA ST, IL-22 expression was higher in RA than either OA or PsA ST, in which IL-22 was strikingly absent.

Conclusions

Elevated frequencies of IL-17 and IL-22 producing CD4+ T cells were a feature of both Ps and PsA. However their differing distribution at disease sites, including lower frequencies of IL-22+ CD4+ T cells in SF compared to skin and PB, and lack of IL-22 expression in ST suggests that Th17 and Th22 cells have common, as well as divergent roles in the pathogenesis of Ps and PsA.     

Evidence of a role for Th17 cells in the breach of immune tolerance in arthritis

Th17 cells are thought to play a pathogenic role in various autoimmune diseases. Cytokines secreted by Th17 cells like IL-17, IL-17F and IL-22 have the capacity to mediate a massive inflammatory response. These proinflammatroy cytokines are likely to mediate the pathogenic potential of Th17 cells. Recent evidence suggests a role for Th17 cells in the breach of immune tolerance. This might shed some new light on the pathogenic role of Th17 cells in autoimmunity.     

HIV-1 diseases progression associated with loss of Th17 cells in subtype 'C' infection

Th17 cells play a crucial role in host immune response. We examined the role of Th17 cells in HIV-1 'subtype-C' infection and report that HIV-1 specific Th17 cells are induced in early infection and slow progressors but are significantly reduced at late stage of infection. There was a further decline in Th17 cells in late stage subjects with gastrointestinal infections. Additionally, we observed expanded population of IL-21 (needed for Th17 population expansion) producing CD4 T cells in early and slow progressors compared to subjects with late stage infection. A significant positive correlation existed between virus specific IL-17 and IL-21 producing CD4 T cells suggesting that HIV-1 infection induces a demand for Th17 cells. A significant negative correlation between virus specific Th17 cells and HIV-1 plasma viral load (pVL) was also observed, indicating a gradual loss of Th17 cells with HIV-1 disease progression.     

Th17 cells in immunity to Candida albicans

Our understanding of immunity to fungal pathogens has advanced considerably in recent years. Particularly significant have been the parallel discoveries in the C-type lectin receptor family and the Th effector arms of immunity, especially Th17 cells and their signature cytokine, IL-17. Many of these studies have focused on the most common human fungal pathogen, Candida albicans, which is typically a commensal microbe in healthy individuals but causes various disease manifestations in immunocompromised hosts, ranging from mild mucosal infections to lethal disseminated disease. Here, we discuss emerging fundamental discoveries with C.?albicans that have informed our overall molecular understanding of fungal immunity. In particular, we focus on the importance of pattern recognition receptor-mediated fungal recognition and subsequent IL-17 responses in host defense against mucosal candidiasis. In light of these recent advances, we also discuss the implications for anticytokine biologic therapy and vaccine development.     

Th17 cells and IL-17 in protective immunity to vaginal candidiasis

Background

Th17 cells play a major role in coordinating the host defence in oropharyngeal candidiasis. In this study we investigated the involvement of the Th17 response in an animal model of vulvovaginal candidiasis (VVC).

Methods

To monitor the course of infection we exploited a new in vivo imaging technique.

Results

i) The progression of VVC leads to a strong influx of neutrophils in the vagina soon after the challenge which persisted despite the resolution of infection; ii) IL-17, produced by vaginal cells, particularly CD4 T cells, was detected in the vaginal wash during the infection, reaching a maximum 14 days after the challenge; iii) The amount and kinetics of IL-23 in vaginal fluids were comparable to those in vaginal cells; iv) The inhibition of Th17 differentiation led to significant inhibition of IL-17 production with consequent exacerbation of infection; v) An increased production of βdefensin 2 was manifested in cells of infected mice. This production was strongly reduced when Th17 differentiation was inhibited and was increased by rIL-17 treatment.

Conclusions

These results imply that IL-17 and Th17, along with innate antimicrobial factors, have a role in the immune response to vaginal candidiasis.     

Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus

Introduction  

Interleukin (IL)-17 is a proinflammatory cytokine that is produced largely by a unique CD4⁺ T-helper (Th) subset called Th17 cells. The development of Th17 cells is suppressed by interferon (IFN)-γ produced by Th1 cells, suggesting cross-regulation between Th17 and Th1 cells. Thus, this study analyzed the balance of CD4⁺ Th17 and Th1 cell responses in peripheral blood from patients with systemic lupus erythematosus (SLE) and healthy subjects.     

TGF-beta-exposed plasmacytoid dendritic cells participate in Th17 commitment

TGF-β is required for both Foxp3(+) regulatory T cell (Treg) and Th17 commitment. Plasmacytoid DCs (pDC) have been shown to participate to both Treg and Th17 commitment as well. However, few studies have evaluated the direct effect of TGF-β on pDC, and to our knowledge, no study has assessed the capacity of TGF-β-exposed pDC to polarize naive CD4(+) T cells. In this paper, we show that TGF-β-treated pDC favor Th17 but not Treg commitment. This process involves a TGF-β/Smad signal, because TGF-β treatment induced Smad2 phosphorylation in pDC and blockade of TGF-β signaling with the SD208 TGF-βRI kinase inhibitor abrogated Th17 commitment induced by TGF-β-treated pDC. Moreover, TGF-β mRNA synthesis and active TGF-β release were induced in TGF-β-treated pDC and anti-TGF-β Ab blocked Th17 commitment. Unexpectedly, TGF-β treatment also induced increased IL-6 production by pDC, which serves as the other arm for Th17 commitment driven by TGF-β-exposed pDC, because elimination of IL-6-mediated signal with either IL-6- or IL-6Rα-specific Abs prevented Th17 commitment. The in vivo pathogenic role of TGF-β-treated pDC was further confirmed in the Th17-dependent collagen-induced arthritis model in which TGF-β-treated pDC injection significantly increased arthritis severity and pathogenic Th17 cell accumulation in the draining lymph nodes. Thus, our data reveal a previously unrecognized effect of TGF-β-rich environment on pDC ability to trigger Th17 commitment. Such findings have implications in the pathogenesis of autoimmune diseases or immune responses against mucosal extracellular pathogens.     

Phenotype switching by inflammation-inducing polarized Th17 cells, but not by Th1 cells

Th1 and Th17 cells are characterized by their expression of IFN-gamma or IL-17, respectively. The finding of Th cells producing both IL-17 and IFN-gamma suggested, however, that certain Th cells may modify their selective cytokine expression. In this study, we examined changes in cytokine expression in an experimental system in which polarized Th1 or Th17 cells specific against hen egg lysozyme induce ocular inflammation in recipient mice expressing hen egg lysozyme in their eyes. Whereas only IFN-gamma was expressed in eyes of Th1 recipient mice, substantial proportions of donor cells expressed IFN-gamma or both IFN-gamma and IL-17 in Th17 recipient eyes. The possibility that nonpolarized cells in Th17 preparations were responsible for expression of IFN-gamma or IFN-gamma/IL-17 in Th17 recipient eyes was contradicted by the finding that the proportions of such cells were larger in recipients of Th17 preparations with 20-25% nonpolarized cells than in recipients of 35-40% preparations. Moreover, whereas incubation in vitro of Th1 cells with Th17-polarizing mixture had no effect on their phenotype, incubation of Th17 with Th1-polarizing mixture, or in the absence of cytokines, converted most of these cells into IFN-gamma or IFN-gamma/IL-17-expressing cells. In addition, Th17 incubated with the Th1 mixture expressed T-bet, whereas no ROR-gamma t was detected in Th1 incubated with Th17 mixture. Thus, polarized Th1 cells retain their phenotype in the tested systems, whereas Th17 may switch to express IFN-gamma or IFN-gamma/IL-17 following activation in the absence of cytokines, or exposure to certain cytokine milieus at the inflammation site or in culture.