胸腺基质淋巴细胞生成素在免疫应答反应中的新功能

发布时间：2018-01-03 09:04

本文关键词：胸腺基质淋巴细胞生成素在免疫应答反应中的新功能　出处：《浙江大学》2012年博士论文　论文类型：学位论文

【摘要】：胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin, TSLP)是一种上皮细胞来源的细胞因子,通过作用于髓样和淋巴样细胞,协调天然免疫和适应性免疫,在起始和促进Th2细胞介导的过敏性炎症中起至关重要的作用。随着研究的不断深入,TSLP作为哮喘和其它过敏性疾病的新型治疗靶标逐渐成为可能。考虑到促炎因子和炎症因子在多种组织中引起TSLP生成,TSLP极有可能在除了由Th2细胞介导的疾病之外的其它炎症中,有更广泛的作用。在本论文中,我们进一步研究了TSLP在过敏性炎症致病机理中的作用,特别是对调节呼吸道免疫耐受和过敏性炎症之间平衡所起的作用,以及TSLP在LPS介导的Th2型炎症中的作用,并研究了在过敏性呼吸道炎症中,TSLP能否促进产生IL-9的Th9细胞的分化和功能。在外周系统中诱导产生抗原特异性的调节性T细胞(iTreg)是维持针对无害抗原的黏膜免疫耐受的重要机制。在本研究中,我们发现在小鼠外周系统中,TSLP抑制了iTreg的生成,其抑制作用大小呈剂量依赖关系。与此相应,在患异位性皮炎(atopic dermatitis)的儿童中,其血清中的TSLP水平显著增加。因此,TSLP抑制呼吸道免疫耐受并造成过敏原致敏,从而导致过敏性呼吸道炎症发生的重要机理之一是TSLP抑制了iTreg的分化。针对无害抗原,TSLP是否以及如何诱生Th2细胞分化,仍不十分清楚。使用OVA和LPS的小鼠鼻腔致敏模型,我们发现TSLP信号仅在低浓度LPS诱导的Th2细胞偏向的呼吸道炎症中所必需,而不被高浓度LPS所诱导的Thl型炎症所需要。我们进一步阐明了,低浓度LPS活化成熟的骨髓来源的树突状细胞(BMDC)表达相对高水平的Tslp和低水平的Il12a,并以依赖于TSLP的方式诱导初始DO11.10T细胞分化成Th2细胞。当过继转移至野生型受体小鼠时,低浓度LPS和OVA激活的DC诱导嗜酸性粒细胞主导的呼吸道炎症,当Tslp缺失的DC被转移时,在受体小鼠中诱生嗜中性粒细胞主导的呼吸道炎症。这些数据表明,在低浓度LPS的刺激下,DC产生的TSLP在诱导Th2细胞的分化中起重要作用,并因此表明,除了抗原/MHCII和共刺激分子之外,TSLP可作为抗原提呈细胞来源的第三方极化信号,来引导效应T细胞的分化。我们发现在体外培养Th9细胞时,TSLP会使Th9细胞增加IL-9的表达,且IL-9的表达量与TSLP剂量呈正相关。过继转移OVA特异性的Th2或Th9细胞至野生型受体中,用OVA或OVA+TSLP呼吸道激发后,TSLP增强了注射Th9细胞的小鼠的IL-9表达及其过敏性炎症,却对被转移Th2细胞的小鼠影响甚微。抗IL-9抗体处理被转移Th9细胞的受体小鼠,则显著降低其肺部炎症。TSLP甚至在TSLP受体缺失的受体小鼠中仍能增强Th9细胞介导的呼吸道炎症,这表明TSLP在体内对Th9细胞有直接作用。进一步的研究表明,在肺部特异性表达的转基因TSLP刺激肺部产生IL-9,而用抗IL-9抗体处理则减弱了TSLP引发的呼吸道炎症。综上所述,我们的研究揭示了TSLP促进Th9细胞的分化和功能,并表明了IL-9在TSLP介导的过敏性炎症中必不可少。
[Abstract]:Thymic stromal lymphopoietin (thymic stromal, lymphopoietin, TSLP) is a cytokine derived from epithelial cells, by acting on myeloid and lymphoid cells that coordinate innate immunity and adaptive immunity, in the initiation and promotion play an important role in Th2 cell mediated allergic inflammation. With the deepening of the study, as TSLP a new target for treatment of asthma and other allergic diseases has become possible. Considering the production of proinflammatory cytokines and inflammatory factors induced by TSLP generated in a variety of tissues, TSLP is very likely in addition to other inflammation mediated by Th2 cells in disease have a broader role. In this thesis, we further study the role of TSLP in pathogenesis of allergic inflammation, especially on the regulation of immune tolerance between respiratory and allergic inflammation and balance the role of TSLP in Th2 mediated by LPS The role of inflammation and the ability of TSLP to promote the differentiation and function of Th9 cells that produce IL-9 in allergic respiratory inflammation.
Induced in the peripheral system for generating antigen-specific regulatory T cells (iTreg) is an important mechanism to maintain the mucosal immune tolerance to innocuous antigens. In this study, we found that in mouse peripheral system, TSLP inhibited the formation of iTreg, its inhibitory effect is dose dependent relationship with this. Accordingly, in patients with atopic dermatitis (atopic dermatitis) in children, the serum level of TSLP was significantly increased. Therefore, TSLP inhibited the immune tolerance and cause respiratory allergen sensitization, which leads to an important mechanism of allergic airway inflammation is one of the TSLP inhibited the differentiation of iTreg.
According to innocuous antigens, whether and how TSLP induced Th2 cell differentiation remains unclear. Mouse nasal hypersensitivity model using OVA and LPS, we found that the required airway inflammation induced by TSLP signaling only in the low concentration of LPS in Th2 cells without being biased, Thl type inflammation induced by high concentration of LPS we need to further clarify. The low concentration of LPS activation and maturation of bone marrow derived dendritic cells (BMDC) express relatively high levels of Tslp and low levels of Il12a, and induce the initial differentiation of DO11.10T cells into Th2 cells in a TSLP dependent manner. When the adoptive transfer to the wild-type receptor in mice, eosinophilic airway inflammation acid granulocyte dominated by low concentrations of LPS and OVA activated DC, when the deletion of the Tslp DC was transferred, in recipient mice induced eosinophilic airway inflammation neutrophil dominant. These data suggest that LPS stimulation at low concentrations The TSLP produced by DC plays an important role in the differentiation of Th2 cells. Therefore, TSLP can be used as the third party polarized signal from antigen presenting cells to guide the differentiation of T cells, except for /MHCII and costimulatory molecules.
We found that Th9 cells cultured in vitro, TSLP can make Th9 cells increase the expression of IL-9, expression of IL-9 and TSLP was dose related. The adoptive transfer of Th2 or Th9 cells to wild-type receptor specific OVA, OVA or OVA+TSLP stimulate the respiratory tract, TSLP enhanced the expression of IL-9 injection of Th9 cells in mice and the allergic inflammation, but little effect on mice were transferred Th2 cells. Anti IL-9 antibody treated by transfer of Th9 cell receptor in mice, significantly reduced the lung inflammation even in the absence of the TSLP receptor.TSLP receptor in mice can enhance airway inflammation mediated by Th9 cells, suggesting that TSLP has a direct effect in vivo. On Th9 cells. Further studies showed that IL-9 TSLP expression in transgenic lung specific stimulation of the lungs, and the use of anti IL-9 antibody treatment attenuates airway inflammation induced by TSLP. In summary, our research The study reveals that TSLP promotes the differentiation and function of Th9 cells, and indicates that IL-9 is essential in the allergic inflammation mediated by TSLP.

【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R392

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