Contribution of IL-12R mediated feedback loop to Th1 cell differentiation

T helper 1 (Th1) cell fate is induced by overlapping signaling pathways, whose kinetic principles and regulatory motifs are largely unknown. We identified a simple positive feedback loop in the STAT4 signaling pathway, whereby activation by IL-12 leads to the increased expression in IL-12 receptor. A computational analysis shows that this feedback loop synergizes with the one mediated by the IFN-gamma secreted by differentiating cells, when the induction of Th1 cell fate is weak. Positive feedback loops are often utilized to enhance phenotypic differentiation. This effect was confirmed by experiments showing that stochastic fluctuations in the expression of IL-12 receptor gene were amplified, leading to two discrete levels of expression in a cell population.     

Th2与ILC2细胞在哮喘模型中的数量及产生细胞因子的比较研究

目的比较过敏原依赖和非依赖性哮喘模型中2型辅助性T细胞(Th2 cell)和固有淋巴样2型细胞(type 2innate lymphoid cell,ILC2)的功能。方法滴鼻法制备过敏原卵清蛋白(ovalbumin,OVA)和上皮源性细胞因子(IL-25、IL-33)诱导的亚急性和慢性哮喘小鼠模型。收集小鼠肺泡灌洗液(bronchoalvelar lavage fluid,BALF)进行细胞计数;取左肺进行石蜡包埋、切片和HE染色;右肺行流式细胞术,以分析在不同时间点各组小鼠Th2细胞和ILC2细胞数目和占肺组织总细胞比例,并对Th2型细胞因子的来源进行分析。结果与生理盐水组相比,各实验组BALF中总细胞数明显增加; HE染色可见OVA、IL-25和IL-33均可诱导哮喘典型病理学改变;各实验组肺组织中Th2细胞与ILC2细胞均明显上升,数量上以Th2细胞为主,两者均可产生Th2型细胞因子IL-5和IL-13,且以Th2细胞为主。而在致哮喘样改变、促进Th2细胞和ILC2细胞在小鼠肺部聚集等方面,以IL-33的效应最强。结论在过敏原OVA和非过敏原IL-25、IL-33诱导的哮喘模型中,Th2型细胞因子主要来源均为Th2细胞,提示Th2细胞在哮喘的发生、发展中起到主要作用。IL-33可能是过敏性和非过敏性哮喘患者个体化治疗的潜在靶点。     

The pathogenesis of thyroid autoimmune diseases: New T lymphocytes – Cytokines circuits beyond the Th1−Th2 paradigm

Autoimmune thyroid disease (AITD) is one of the most common organ-specific autoimmune disorders. It mainly manifests as Hashimoto's thyroiditis (HT) and Graves’ disease (GD). HT is characteristic of hypothyroidism resulting from the destruction of the thyroid while GD is characteristic of hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. T lymphocytes and their secretory cytokines play indispensable roles in modulating immune responses, but their roles are often complex and full of interactions among distinct components of the immune system. Dysfunction of these T cells or aberrant expressions of these cytokines can cause the breakdown of immune tolerance and result in aberrant immune responses during the development of AITDs. This review summarizes recently identified T subsets and related cytokines and their roles in the pathogenesis of AITDs with the hope to provide a better understanding of the precise roles of notably identified T subsets in AITDs and facilitate the discovery of functional molecules or novel immune therapeutic targets for AITDs.     

Stereoselective Synthesis of threo-4,4,4-Trichlorothreonine

threo-4,4,4-Trichlorothreonine was synthesized completely stereoselectively through trans-4-alkoxycarbonyl-5-trichloromethyl-2-oxazoline, which was prepared almost quantitatively by the reaction of 2-isocyano acetate with chloral in the presence of an organic base. Several derivatives of these compounds were also synthesized.

Furthermore, the stereochemistry of the resulting trichlorocompounds was chemically elucidated. The trichlorothreonine was easily converted into threo-threonine by hydrogenation over Pd/C in the presence of NaHCO₈.     

Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses

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Crosstalk between ILC2s and Th2 cells varies among mouse models

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Th2型细胞因子在支气管哮喘发作过程中的表达

支气管哮喘是由多种细胞特别是肥大细胞、嗜酸性粒细胞和T淋巴细胞参与的慢性气道炎症。对支气管哮喘发病机制的认识近年有重大改变 ,Th2型细胞的作用被认为是支气管哮喘发作过程的中心 ,综述了由Th2型细胞产生的细胞因子在支气管哮喘发病过程中的作用及意义。     

滤泡辅助性T细胞分化和功能的研究进展

滤泡辅助性T细胞(Tfollicular helper cells,TFH细胞)是新近发现的一种CD4+辅助性T细胞亚群,具有不同于其他亚群的独特功能:迁移到B淋巴滤泡并辅助B淋巴细胞产生抗体。在短短的几年里面,已有大量针对滤泡辅助性T细胞分化与功能的研究。该文将对滤泡辅助性T细胞的最新研究进展作一综述。     

IL-17 inhibits human Th1 differentiation through IL-12Rβ2 downregulation

Th17 cells are critical in adaptive immunity and autoimmune disease. The polarized development of Th17, Th1 and Th2 cells is dependent on counterregulatory effects on each other. Whereas IFN-γ inhibits Th17 development, the effect of IL-17 in human Th1 development is not known. We report a novel negative regulatory role of IL-17 on IL-12Rβ2 expression associated with reduced IL-12 responsiveness. IL-17 decreased IL-12-induced IFN-γ expression in PBMC and developing Th1 cells, associated with a selective reduction in IL-12Rβ2, and not IL-23R, IL-12Rβ1 or T-bet. Counterregulatory effects of human Th17 on Th1 lineage cytokines may contribute to lineage divergence. In autoimmune disease, IL-17 may reinforce its own developmental programme by reducing IL-12 responsiveness, thus limiting inhibitory effects of IFN-γ on Th17 development.     

Basophil-associated OX40 Ligand Participates in the Initiation of Th2 Responses during Airway Inflammation

Asthma is characterized by increased airway submucosal infiltration of T helper (Th) cells and myeloid cells that co-conspire to sustain a chronic inflammation. While recent studies have demonstrated that the myeloid basophils promote Th2 cells in response to various types of allergens, the underlying mechanisms are poorly understood. Here, we found for the first time that in a mouse model of allergic asthma basophils highly expressed OX40 ligand (OX40L) after activation. Interestingly, blockade of OX40-OX40L interaction suppressed basophils-primed Th2 cell differentiation in vitro and ameliorated ovalbumin (OVA)-induced allergic eosinophilic inflammation mediated by Th2 activation. In accordance, the adoptive transfer of basophils derived from mediastinal lymph nodes (MLN) of OVA-immunized mice triggered a robust Th2 response and eosinophilic inflammation in wild-type mice but largely muted in OX40^−/− mice and mice receiving OX40L-blocked basophils. Taken together, our results reveal a critical role of OX40L presented by the activated basophils to initiate Th2 responses in an allergic asthma model, implicating OX40-OX40L signaling as a potential therapeutic target in the treatment of allergic airway inflammation.     

Constitutive expression of CIITA directs CD4 T cells to produce Th2 cytokines in the thymus

We generated mice expressing a human type III CIITA transgene (CIITA Tg) under control of the CD4 promoter to study the role of CIITA in CD4 T cell biology. The transgene is expressed in peripheral CD4 and CD8 T cells, as well as in thymocytes. When CD4 T cells were differentiated towards the Th2 lineage, both control and CIITA Tg Th2 cells expressed similar levels of Th2 cytokines. Th1 cells from control and CIITA Tg mice cells produced comparable levels of IFN-gamma. CIITA Tg Th1 cells also expressed IL-4, IL-5, and IL-13 in the absence of Stat6. There was an approximate 10-fold increase in the number of peripheral na?ve CD4 T cells and NK1.1- thymocytes producing IL-4 from CIITA Tg mice compared to control mice. Finally, Th1 cells from irradiated control mice reconstituted with CIITA Tg bone marrow displayed the same cytokine production profiles as Th1 cells from CIITA Tg mice. Together, our data demonstrate that CIITA expression pre-disposes CD4 T cells to produce Th2 type cytokines. Moreover, phenotypic similarities between Th1 cells expressing the CIITA transgene and CIITA deficient Th1 cells suggest that the role of CIITA in cytokine regulation is complex and may reflect both direct and indirect mechanisms of T cell development and differentiation.     

Mir-29b mediates the regulation of Nrf2 on airway epithelial remodeling and Th1/Th2 differentiation in COPD rats

COPD, or Chronic obstructive pulmonary disease, is an inflammation-related disease and lead to cachexia and muscle wasting. Altered nuclear factor erythroid 2-related factor 2 (Nrf2) expression is found in patients of COPD because it is involved in pulmonary protective effects. MiR-29b could be activated by Nrf2. We hypothesized that miR-29b might mediate the regulation of Nrf2 on Th1/Th2 differentiation and airway epithelial remodeling in COPD rats. SD rats were exposed to smoke for COPD induction. Expression of Nrf2 mRNA and miR-29b in lung tissues was quantified. Expression of Nrf2 and matrix metalloproteinase 2 (MMP2) were also detected by immunohistochemistry and western blot. Th1 markers and Th2 markers were measured by ELISA in peripheral blood. Flow cytometry was used to detect the Th1/Th2 ratio. miR-29b and Nrf2 was manipulated at mRNA level in A549 cells using transfection. Cellular growth and migration were measured in transfectants. In lung tissues of COPD rats, expression of Nrf2 and miR-29b decreased. MMP2, a target of miR-29b, had an opposite expression to miR-29b in peripheral blood. Levels of inflammatory factors and Th1/Th2 ratio increased. MiR-29b mediated the regulation of Nrf2 on remodeling of lung epithelial cells. Blocking Nrf2 expression in A549 cells led to the opposite expression of miR-29b and further decreased MMP2 production; meanwhile, cell growth and motility were improved. Different miR-29b levels affected MMP2 expression and cellular characteristics. The findings suggested that miR-29b was a regulator the pathological progress of COPD. It mediates the effect of Nrf2 on Th1/Th2 differentiation and on remodeling process of airway epithelial cells.     

Potentiation of Th17 cytokines in aging process contributes to the development of colitis

Th17 cells, which produce IL-17 and IL-22, promote autoimmunity in mice and have been implicated in the pathogenesis of autoimmune/inflammatory diseases in humans. However, the Th17 immune response in the aging process is still not clear. In the present study, we found that the induction of IL-17-produing CD4⁺ T cells was significantly increased in aged individuals compared with young healthy ones. The mRNA expression of IL-17, IL-17F, IL-22, and RORC2 was also significantly increased in aged people. Similar to humans, Th17 cells as well as mRNAs encoding IL-17, IL-22 and RORγt were dramatically elevated in naïve T cells from aged mouse compared to young ones. In addition, CD44 positive IL-17-producing CD4⁺ T cells were significantly higher in aged mice, suggesting that memory T cells are an important source of IL-17 production. Furthermore, the percentage of IL-17-produing CD4⁺ T cells generated in co-culture with dendritic cells from either aged or young mice did not show significant differences, suggesting that dendritic cells do not play a primary role in the elevation of Th17 cytokines in aged mouse cells. Importantly, transfer of CD4⁺CD45Rb^hi cells from aged mice induced more severe colitis in RAG^−/− mice compared to cells from young mice, Taken together, these results suggest that Th17 immune responses are elevated in aging humans and mice and may contribute to the increased development of inflammatory disorders in the elderly.     

Th22细胞与支气管哮喘

支气管哮喘是一种临床上常见的呼吸道疾病,研究发现CD4＋T细胞在哮喘的发病过程中起重要作用。Th22细胞是最近发现的一类CD4＋T细胞功能亚群之一,其主要效应因子IL-22在炎症性疾病、组织修复、创口愈合及自身免疫性疾病中起重要作用,但其具体机制尚未完全清楚。从Th22的细胞因子来源、生物学特性、分化和调控出发,简要探讨Th22细胞与哮喘之间的可能关系。     

支气管哮喘患儿肺功能状态及Th1Th2指标的变化观察

目的:观察支气管哮喘患儿肺功能状态及Th1Th2指标的变化情况。方法:选取2013年10月~2015年8月本院诊治的65例支气管哮喘患儿为观察组,另选择同期接受体检的健康同龄儿童65名为对照组。比较两组患儿肺功能状态及Th1Th2指标,观察不同严重程度及分期支气管哮喘患儿的肺功能状态及Th1Th2指标。结果:观察组患儿肺功能指标及血清Th1Th2指标均低于对照组,差异具有统计学意义(P0.05);观察组患儿发作期肺功能指标及血清Th1Th2指标明显低于缓解期,差异具有统计学意义(P0.05);重度患儿肺功能指标及血清Th1Th2指标均低于轻度及中度患儿,差异具有统计学意义(P0.05);中度患儿肺功能指标及血清Th1Th2指标低于轻度患儿,差异具有统计学意义(P0.05)。结论:支气管哮喘患儿肺功能状态及Th1Th2指标的变化较大,且疾病分期与疾病严重程度对其检测结果也有较大影响。