T-zone localized monocyte-derived dendritic cells promote Th1 priming to Salmonella

Control of intracellular Salmonella infection requires Th1 priming and IFN‐γ production. Here, we show that efficient Th1 priming after Salmonella infection requires CD11c⁺CD11b^hiF4/80⁺ monocyte‐derived dendritic cells (moDCs). In non‐infected spleens, moDCs are absent from T‐cell zones (T zones) of secondary lymphoid tissues, but by 24 h post‐infection moDCs are readily discernible in these sites. The accumulation of moDCs is more dependent upon bacterial viability than bacterial virulence. Kinetic studies showed that moDCs were necessary to prime but not sustain Th1 responses, while ex vivo studies showed that antigen‐experienced moDCs were sufficient to induce T‐cell proliferation and IFN‐γ production via a TNF‐α‐dependent mechanism. Importantly, moDCs and cDCs when co‐cultured induced superior Th1 differentiation than either subset alone, and this activity was independent of TNF‐α. Thus, optimal Th1 development to Salmonella requires the rapid accumulation of moDCs within T zones and their collaboration with cDCs.     

IL-23-dependent IL-17 drives Th1-cell responses following Mycobacterium bovis BCG vaccination

The generation of effective type 1 T helper (Th1)-cell responses is required for immunity against intracellular bacteria. However, some intracellular bacteria require interleukin (IL)-17 to drive Th1-cell immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL-17 to drive Th1-cell responses is a host mechanism to overcome bacteria-induced IL-10 inhibitory effects. We show that BCG-induced prostaglandin-E2 (PGE2) promotes the production of IL-10 which limits Th1-cell responses, while simultaneously inducing IL-23 and Th17-cell differentiation. The ability of IL-17 to downregulate IL-10 and induce IL-12 production allows the generation of subsequent Th1-cell responses. Accordingly, BCG-induced Th17-cell responses precede the generation of Th1-cell responses in vivo, whereas the absence of the IL-23 pathway decreases BCG vaccine-induced Th17 and Th1-cell immunity and subsequent vaccine-induced protection upon M. tuberculosis challenge. Importantly, in the absence of IL-10, BCG-induced Th1-cell responses occur in an IL-17-independent manner. These novel data demonstrate a role for the IL-23/IL-17 pathway in driving Th1-cell responses, specifically to overcome IL-10-mediated inhibition and, furthermore, show that in the absence of IL-10, the generation of BCG-induced Th1-cell immunity is IL-17 independent.     

解脲脲原体GrpE蛋白促进小鼠树突状细胞成熟并诱导Th1型免疫应答

目的:探讨解脲脲原体GrpE蛋白( Ureaplasma urealyticum GrpE, Uu-GrpE)对树突状细胞成熟的影响及其对T细胞极化的作用。 方法:表达纯化 Uu-GrpE蛋白并利用Western blot鉴定。分离培养小鼠骨髓来源树突状细胞(bone ma...     

Th17细胞与Th1细胞在慢性阻塞性肺疾病炎症发病机制中的调控作用

慢性阻塞性肺疾病(COPD)发病的分子机制目前仍不甚清楚,大量证据表明,T淋巴细胞介导的免疫反应贯穿于COPD的各个阶段,导致炎症反应持续放大.近来研究发现,Th1细胞和Th17细胞均参与了COPD的免疫发病过程,通过相互间作用调控COPD的炎症反应.因此,深入了解COPD炎症发病过程中Th17、Th1细胞免疫应答特征、分化及调控功能,对探讨COPD的致病机制以及免疫调节治疗的靶点具有重要意义.     

Th17 and Th1 Lymphocytes Are Correlated with Chronic Periodontitis

T cells are involved in the homeostasis of periodontal tissues and mediate bone loss in periodontitis, but the involvement of T-helper cells in chronic periodontitis (CP) in a Chinese population is still unclear. This study aimed to assess the distribution of peripheral and local T helper (Th17) and Th1 in CP. Sixty-eight patients with CP and 43 healthy controls were recruited from April 2012 to July 2014 at the Department of Stomatology, People’s Hospital of Xinjiang Uygur Autonomous Region (China). The proportions of Th17 (CD3⁺CD4⁺IL-17⁺) and Th1 (CD3⁺CD4⁺IFN-γ⁺) T-cells in peripheral blood samples were assessed by flow cytometry. Immunohistochemistry was used to quantify interleukin-17 (IL-17) and interferon-gamma (IFN-γ) protein levels in gingival biopsy samples. mRNA levels of IL-17, IFN-γ RORγt, and T-bet in gingival biopsy samples were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The proportions of circulating Th17 cells and Th1 cells were both more abundant in CP patients than in controls (Th17: 1.05% ± 0.87% vs. 0.62% ± 0.49%, P < 0.01; Th1: 13.93% ± 7.94% vs. 8.22% ± 4.50%, P < 0.001). Positive correlations were obtained between the proportion of circulating Th17 cells and probing depth (PD) (r = 0.320, P = 0.001) and between the proportion of circulating Th1 cells and PD (r = 0.372, P < 0.001). IL-17 and IFN-γ protein levels in gingival biopsy samples were markedly increased in CP compared to controls (both P < 0.05). Relative IFN-γ, IL-17A, and T-bet mRNA levels in CP biopsies were higher compared to controls (all P < 0.05). These results suggest that elevated peripheral and local Th17 and Th1 cells might be involved in the pathogenesis of CP.     

TLR ligands of ryegrass pollen microbial contaminants enhance Th1 and Th2 responses and decrease induction of Foxp3hi regulatory T cells

Microbial contamination of grass pollens could affect sensitization, subsequent allergic response, and efficacy of allergen‐specific immunotherapy. We investigated whether bacterial immunomodulatory substances can direct PBMC responses of allergic and nonatopic subjects against ryegrass pollen (RGP) toward Th1, Th2, or regulatory T (Treg) cells. Aqueous extracts of RGP with high or low LPS were fractionated into large and small molecular weight (MW) components by diafiltration. CFSE‐labeled PBMCs from allergic and nonatopic subjects were stimulated with RGP extracts (RGPEs) and analyzed for cytokine secretion and T‐cell responses. High LPS RGPE increased IFN‐γ⁺ Th1 and IL‐4⁺ Th2 effector cell induction and consistently decreased CD4⁺Foxp3^hi Treg‐cell induction. IL‐10‐producing T‐cell frequency was unaltered, but IL‐10 secretion was increased by high LPS RGPE. RGPE‐stimulation of TLR‐transfected cell lines revealed that high LPS pollen also contained a TLR2‐ligand, and both batches a TLR9‐ligand. Beta‐1,3‐glucans were detected in large and small MW fractions and were also T‐cell stimulatory. In conclusion, coexposure to allergen and proinflammatory microbial stimuli does not convert an established Th2‐ into a Th1‐response. Instead, proinflammatory responses are exacerbated and Foxp3^hi Treg‐cell induction is decreased. These findings show that adjuvants for specific immunotherapy should enhance Treg cells rather than target immune deviation from Th2 to Th1.     

Natural killer T-cell characterization through gene expression profiling: an account of versatility bridging T helper type 1 (Th1), Th2 and Th17 immune responses

Natural killer T (NKT) cells constitute a distinct lymphocyte lineage at the interface between innate and adaptive immunity, yet their role in the immune response remains elusive. Whilst NKT cells share features with other conventional T lymphocytes, they are unique in their rapid, concomitant production of T helper type 1 (Th1) and Th2 cytokines upon T-cell receptor (TCR) ligation. In order to characterize the gene expression of NKT cells, we performed comparative microarray analyses of murine resting NKT cells, natural killer (NK) cells and naïve conventional CD4⁺ T helper (Th) and regulatory T cells (Treg). We then compared the gene expression profiles of resting and alpha-galactosylceramide (αGalCer)-activated NKT cells to elucidate the gene expression signature upon activation. We describe here profound differences in gene expression among the various cell types and the identification of a unique NKT cell gene expression profile. In addition to known NKT cell-specific markers, many genes were expressed in NKT cells that had not been attributed to this population before. NKT cells share features not only with Th1 and Th2 cells but also with Th17 cells. Our data provide new insights into the functional competence of NKT cells which will facilitate a better understanding of their versatile role during immune responses.     

Ganglioside-exposed dendritic cells inhibit T-cell effector function by promoting regulatory cell activity

Tumour pathogenesis is characterized by an immunosuppressive microenvironment that limits the development of effective tumour‐specific immune responses. This is in part the result of tumour‐dependent recruitment and activation of regulatory cells, such as myeloid‐derived suppressor cells and regulatory T cells in the tumour microenvironment and draining lymph nodes. Shedding of gangliosides by tumour cells has immunomodulatory properties, suggesting that gangliosides may be a critical factor in initiating an immunosuppressive microenvironment. To better define the immunomodulatory properties of gangliosides on antigen‐specific T‐cell activation and development we have developed an in vitro system using ganglioside‐treated murine bone‐marrow‐derived dendritic cells to prime and activate antigen‐specific CD4⁺ T cells from AND T‐cell receptor transgenic mice. Using this system, ganglioside treatment promotes the development of a dendritic cell population characterized by decreased CD86 (B7‐2) expression, and decreased interleukin‐12 and interleukin‐6 production. When these cells are used as antigen‐presenting cells, CD4 T cells are primed to proliferate normally, but have a defect in T helper (Th) effector cell development. This defect in Th effector cell responses is associated with the development of regulatory T‐cell activity that can suppress the activation of previously primed Th effector cells in a contact‐dependent manner. In total, these data suggest that ganglioside‐exposed dendritic cells promote regulatory T‐cell activity that may have long‐lasting effects on the development of tumour‐specific immune responses.     

Aire deficient dendritic cells promote the T follicular helper cells differentiation

Autoimmune regulator (Aire), primarily expressed in medullary thymic epithelial cells (mTECs), maintains central immune tolerance through the clearance of self-reactive T cells. Aire can also be expressed in dendritic cells (DCs), and DCs can mediate T follicular helper (T_FH) cell differentiation and self-reactive B cell activation through inducible costimulator molecule ligand (ICOSL) and interleukin 6 (IL-6), which can cause autoimmune diseases. To confirm whether Aire in DCs affects T_FH cell differentiation and to determine the role of Aire in the maintenance of peripheral immune tolerance, this study observed the effects of Aire deficiency on T_FH cells using Aire knockout mice. The results showed that Aire deficiency caused increased number of T_FH cells, both in vivo and in vitro. Further studies showed that Aire deficiency promoted T_FH differentiation through the upregulation of ICOSL and IL-6 in DCs. Thus Aire could suppress the expression of ICOSL and IL-6 to inhibit T_FH cell differentiation.     

The inflammasome drives protective Th1 and Th17 cellular responses in disseminated candidiasis

The Nlrp3 inflammasome has been proposed to play an important role in antifungal host defense. However, studies exploring the role of the inflammasome in antifungal host defense have been limited to the direct effects on IL-1β processing. Although IL-1β has important direct effects on the innate immune response, important effects of the caspase-1-dependent cytokines IL-1β and IL-18 are exerted on the initiation of the adaptive Th1 and Th17 cellular responses. No studies have been employed to assess the impact of the inflammasome on the Th1/Th17 defense mechanisms in vivo during candidiasis. In the present study, we demonstrate an essential role for caspase-1 and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) in disseminated candidiasis through regulating antifungal Th1 and Th17 responses. Caspase-1(-/-) and ASC(-/-) mice display diminished Th1/Th17 responses, followed by increased fungal outgrowth and lower survival. These observations identify a critical role for the inflammasome in controlling protective adaptive immune responses during invasive fungal infection.     

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis

Autoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). We examined the stimulatory effect of human myelin basic protein (MBP) on mononuclear cell (MNC) cultures from 22 patients with MS and 22 sex-matched and age-matched healthy individuals, and related the patient responses to disease activity, as indicated by magnetic resonance imaging. The MBP induced a dose-dependent release of interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) by patient-derived MNCs. The patients' cells produced higher amounts of IFN-gamma and TNF-alpha, and lower amounts of IL-10, than cells from healthy controls (P<0.03 to P<0.04). Five patients with MS and no controls, displayed MBP-induced CD4+ T-cell proliferation. These high-responders exhibited enhanced production of IL-17, IFN-gamma, IL-5 and IL-4 upon challenge with MBP, as compared with the remaining patients and the healthy controls (P<0.002 to P<0.01). A strong correlation was found between the MBP-induced CD4+ T-cell proliferation and production of IL-17, IFN-gamma, IL-5 and IL-4 (P<0.0001 to P<0.01) within the patient group, and the production of IL-17 and IL-5 correlated with the number of active plaques on magnetic resonance images (P=0.04 and P=0.007). These data suggest that autoantigen-driven CD4+ T-cell proliferation and release of IL-17 and IL-5 may be associated with disease activity. Larger studies are needed to confirm this.     

Human dendritic cells activated with MV130 induce Th1, Th17 and IL‐10 responses via RIPK2 and MyD88 signalling pathways

Recurrent respiratory tract infections (RRTIs) are the first leading cause of community‐ and nosocomial‐acquired infections. Antibiotics remain the mainstay of treatment, enhancing the potential to develop antibiotic resistances. Therefore, the development of new alternative approaches to prevent and treat RRTIs is highly demanded. Daily sublingual administration of the whole heat‐inactivated polybacterial preparation (PBP) MV130 significantly reduced the rate of respiratory infections in RRTIs patients, however, the immunological mechanisms of action remain unknown. Herein, we study the capacity of MV130 to immunomodulate the function of human dendritic cells (DCs) as a potential mechanism that contribute to the clinical benefits. We demonstrate that DCs from RRTIs patients and healthy controls display similar ex vivo immunological responses to MV130. By combining systems biology and functional immunological approaches we show that MV130 promotes the generation of Th1/Th17 responses via receptor‐interacting serine/threonine‐protein kinase‐2 (RIPK2)‐ and myeloid‐differentiation primary‐response gene‐88 (MyD88)‐mediated signalling pathways under the control of IL‐10. In vivo BALB/c mice sublingually immunized with MV130 display potent systemic Th1/Th17 and IL‐10 responses against related and unrelated antigens. We elucidate immunological mechanisms underlying the potential way of action of MV130, which might help to design alternative treatments in other clinical conditions with high risk of recurrent infections.     

Lactobacillus acidophilus strain L-92 induces apoptosis of antigen-stimulated T cells by modulating dendritic cell function

Beneficial effects of lactobacilli have been reported for patients with allergic diseases and intestinal disorders such as inflammatory bowel disease. However, it is not fully understood how such bacteria influence the immunologic response. For this purpose, we investigated the effect of Lactobacillus acidophilus strain L-92 (L-92) on antigen-stimulated T cell responses in vitro and in vivo. In vitro, L-92 decreased the proliferation of CD4⁺ T cells stimulated with antigen, and also induced apoptosis of antigen-stimulated T cells. On the other hand, interferon (IFN)-γ secretion from naïve T cells was increased while interleukin (IL)-4 secretion was decreased by L-92. Co-culture with L-92 induced apoptosis of differentiated Th1 and Th2 cells. The degree of apoptosis induction was higher in Th2 cells. Moreover, L-92 up-regulated the expression of B7-H1 and down-regulated that of B7-H2 on dendritic cells (DCs), and DCs exposed to L-92 also induced apoptosis of antigen-stimulated T cells. Finally, orally administered L-92 induced apoptosis of OVA-specific TCR Tg T cells. These results indicate that L-92 attenuates the CD4⁺ T cell response by inducing DC-mediated apoptosis and that it might exert beneficial effects in patients with diseases resulting from a hyper-response of CD4⁺ T cells.     

急性缺血性脑卒中大鼠脑组织中Th17/Treg的变化

目的:免疫炎症反应在急性缺血性脑卒中的病理生理过程中发挥着重要的作用。具有促炎作用的辅助性T细胞17(Th17)及维持免疫耐受的调节性T细胞(Treg)是体内重要的2种免疫细胞。Th17/Treg细胞平衡是机体维持正常免疫的基础。本研究探讨急性缺血性脑卒中大鼠脑组织中Th17/Treg的变化。方法:采用线栓法制备SD大鼠急性大脑中动脉闭塞(middle cerebral artery occlusion,MCAO)模型,以假手术组作为对照组。在MCAO术后3 d利用TTC染色观察各组大鼠脑梗死体积;采用ELISA测定脑组织中白细胞介素17A(IL-17A)和IL-10蛋白的含量;采用RT-qPCR测定脑组织中IL-17、IL-10、Foxp3和RORγt的mRNA表达水平;采用流式细胞术测定脑组织中Th17细胞和Treg细胞的比例变化。结果:与假手术组相比,MCAO组大鼠脑组织中IL-17A的含量增加,IL-10的含量减少(P0.05);RORγt和IL-17的mRNA表达水平上调(P0.05),Foxp3和IL-10的mRNA表达水平下调(P0.05);脑组织Th17细胞增多,Treg细胞明显减少(P0.05),Th17/Treg比值升高(P0.05)。结论:急性缺血性脑卒中大鼠脑组织Th17细胞增多,Treg细胞减少,表明脑梗死后大鼠脑组织中Th17/Treg的平衡被破坏,免疫炎症反应被激活。     

Pituitary adenylate cyclase-activating peptide and vasoactive intestinal polypeptide bias Langerhans cell Ag presentation toward Th17 cells

Epidermal Langerhans cells (LCs) are dendritic APCs that play an important role in cutaneous immune responses. LCs are associated with epidermal nerves and the neuropeptides vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) inhibit LC Ag presentation for Th1-type immune responses. Here, we examined whether PACAP or VIP modulates LC Ag presentation for induction of IL-17A-producing CD4(+) T cells. Treatment with VIP or PACAP prior to in vitro LC Ag presentation to CD4(+) T cells enhanced IL-17A, IL-6, and IL-4 production, decreased interferon (IFN)-γ and interleukin (IL)-22 release, and increased RORγt and Gata3 mRNA expression while decreasing T-bet expression. The CD4(+) T-cell population was increased in IL-17A- and IL-4-expressing cells and decreased in IFN-γ-expressing cells. Addition of anti-IL-6 mAb blocked the enhanced IL-17A production seen with LC preexposure to VIP or PACAP. Intradermal administration of VIP or PACAP prior to application of a contact sensitizer at the injection site, followed by harvesting of draining lymph node CD4(+) T cells and stimulation with anti-CD3/anti-CD28 mAbs, enhanced IL-17A and IL-4 production but reduced production of IL-22 and IFN-γ. PACAP and VIP are endogenous mediators that likely regulate immunity and immune-mediated diseases within the skin.     

Th17 cells: new players in asthma pathogenesis

CD4+ T effector lymphocytes are distinguished in different subsets on the basis of their patterns of cytokine secretion. Th1 cells, thank to IFN-γ production, are responsible for cell-mediated immunity against intracellular pathogens, Th2 cells, through the production of IL-4, provide some degree of protection against helminthes, and Th17 cells, via IL-17, promote neutrophils recruitment for the clearance of bacteria and fungi. However, beyond their protective role, these T-helper subsets can also be involved in the pathogenesis of several inflammatory diseases. Asthma is an inflammatory disease characterized by different clinical phenotypes. Allergic asthma is the result of an inflammatory process driven by allergen-specific Th2 lymphocytes, whereas Th17 cells are mainly involved in those forms of asthma, where neutrophils more than eosinophils, contribute to the inflammation. The identification in allergic asthma of Th17/Th2 cells, able to produce both IL-4 and IL-17, is in keeping with the observation that different clinical phenotypes can coexist in the same patient. In conclusion, a picture in which different T-cell subpopulations are active in different phase of bronchial asthma is emerging, and the wide spectrum of clinical phenotypes is probably the expression of different cellular characters playing a role in lung inflammation.     

C5a receptor‐deficient dendritic cells promote induction of Treg and Th17 cells

C5a is a proinflammatory mediator that has recently been shown to regulate adaptive immune responses. Here we demonstrate that C5a receptor (C5aR) signaling in DC affects the development of Treg and Th17 cells. Genetic ablation or pharmacological targeting of the C5aR in spleen‐derived DC results in increased production of TGF‐β leading to de novo differentiation of Foxp3⁺ Treg within 12 h after co‐incubation with CD4⁺ T cells from DO11.10/RAG2^?/? mice. Stimulation of C5aR^?/? DC with OVA and TLR2 ligand Pam₃CSK₄ increased TGF‐β production and induced high levels of IL‐6 and IL‐23 but only minor amounts of IL‐12 leading to differentiation of Th cells producing IL‐17A and IL‐21. Th17 differentiation was also found in vivo after adoptive transfer of CD4⁺ Th cell into C5aR^?/? mice immunized with OVA and Pam₃CSK₄. The altered cytokine production of C5aR^?/? DC was associated with low steady state MHC class II expression and an impaired ability to upregulate CD86 and CD40 in response to TLR2. Our data suggest critical roles for C5aR in Treg and Th17‐cell differentiation through regulation of DC function.     

肿瘤通过抑制树突状细胞功能逃避免疫监视的研究进展

树突状细胞(DC)在T细胞介导的免疫反应中起核心作用,可在体内外诱导强烈的抗肿瘤免疫反应.DC作为恶性肿瘤免疫治疗因子被广泛的研究.如今,开发了多种基于DC的抗肿瘤免疫治疗.然而肿瘤也会影响宿主的造血功能以及导致大量未成熟和免疫耐受的DC产生,这些直接抑制免疫反应.了解肿瘤相关DC的免疫抑制作用机制,可提高对肿瘤免疫逃逸的认识.