Th17细胞的研究进展

CD4^＋T细胞在免疫防御中起了核心的作用。迄今为止已经证明至少存在4种不同的CD4^＋T细胞亚群——Th1、Th2、Th17和调节性T细胞（Treg）。其中,Th17细胞是最近研究发现的一种新型的CD4^＋效应T细胞,该细胞是由天然T细胞前体分化而来,具有独立的分化和发育调节机制,并产生特征性的IL-17效应因子,在自身免疫性、感染性疾病和移植排斥中发挥重要的作用。然而,关于Th17介导的免疫反应的调控以及Th17细胞与其它T细胞亚群的相互作用等许多有趣的疑问尚需解答。     

CD226 对 CD4+T 细胞调节作用的研究进展

CD226 为表达于NK 细胞、T 细胞、单核细胞等多种免疫细胞膜上的一种玉型跨膜糖蛋白,与配体CD112 或CD155 结合后,通过介导多种免疫细胞的分化、增殖和功能调节来参与机体多项生理和病理活动。本文围绕CD226 对于CD4+ T 细胞的免疫调控作用和参与疾病进程的研究进展展开综述,重点阐明CD226 参与初始CD4+ T 细胞增殖分化、Th1/ Th2/Th17 细胞极化过程和对调节性T 细胞的调控作用。     

T细胞在多发性硬化发病机制中作用的研究进展

多发性硬化（MS）是临床常见的炎性、脱髓鞘性中枢神经系统（CNS）退行性变,通常认为是T细胞介导的自身免疫性疾病,但其具体病因和发病机制尚不清楚.近年来研究表明,多个亚型的T细胞均参与了MS的发病及其病程的调控.其中包括CD4^＋Th1细胞、CD8^＋T细胞、Th17细胞、CD16＋γδ T细胞、Th2细胞、调节性CD4＋T细胞、NK T细胞、CD8＋调节性T细胞等,因而研究MS了发病机制具有重要意义.     

Th17细胞的分化调控与自身免疫性疾病

Th17细胞是最近发现的一种在分化和功能上均不同于Th1和Th2的新型CD4＋T细胞亚群.该群细胞以主要分泌细胞因子IL-17而得名.IL-6、TGF-β、IL-21及IL-23等对Th17细胞的分化调控发挥重要作用.研究表明,Th17细胞可参与多种自身免疫性疾病的发生、发展与转归.     

C D4＋ T细胞亚群在类风湿关节炎中的研究

类风湿关节炎（ rheumatoid arthritis, RA）是由多因素共同作用引起的自身免疫性疾病,至今发病机制仍未完全阐明, CD4＋T细胞在RA的发生发展中发挥重要作用。早期发现Th1／Th2细胞后,新的CD4＋T细胞亚群不断被发现,包括Th17细胞、 Treg细胞、 Th22细胞、 Th9细胞和Tfh细胞。不同CD4＋T细胞亚群在RA中表达异常,深入研究不同亚群CD4＋T细胞在RA中的作用可为RA的发病机制提供线索。     

T细胞免疫球蛋白粘蛋白分子-4在免疫应答中的作用以及与相关疾病的关系

T细胞免疫球蛋白粘蛋白分子（T-cell immunoglobulin and mucin-domain-containing molecule, TIM）基因是近年来发现的新基因家族,其在调节免疫应答中发挥重要的作用。 TIM-4是TIM家族成员之一,仅表达在巨噬细胞和活化的树突状细胞（ dendritic cell, DC）表面,能够调节T细胞,抑制初始CD4＋T细胞和Th17细胞,增加Th2细胞。 TIM-1与TIM-4相互作用可调节T细胞活化增殖,调节Th1／Th2细胞平衡。此外, TIM-4可与磷脂酰丝氨酸结合,促进巨噬细胞对凋亡细胞的吞噬作用。已经发现TIM-4的调节异常与自身免疫性疾病、过敏性疾病以及肿瘤等有关。因此,了解TIM-4作用于相关受体的机制,可能为免疫介导性疾病调控治疗提供更多的靶点和途径。     

Th17细胞及IL-17与系统性红斑狼疮

系统性红斑狼疮（SLE）是多种因素相互作用引起的自身免疫性疾病,其发病机制复杂。Th17细胞是最近发现的CD4^＋效应T细胞的新亚群。初始T细胞在TGF—B和IL-6的共同作用下分化发育成为Th17细胞,后者可以分泌IL-17、IL-21、IL-22等多种细胞因子。其中IL-17在多种自身免疫疾病（比如类风湿关节炎和Crohn’s病）中起关键作用,但在SLE中的作用尚不清晰。     

Th9细胞与自身免疫性疾病

Th1、Th2、Th17和调节性T细胞（Treg）亚群是CD4＋T细胞亚群中的重要成员,其参与了人类及动物自身免疫性疾病的发病过程.既往认为,IL-9是由CD4＋Th2细胞分泌的细胞因子,是机体免疫应答中重要的调节因子.最近研究表明,机体内可能存在着一群新型的具有分泌IL-9和IL-10能力的CD4＋Th细胞亚群,称之为＂Th9＂细胞.该细胞亚群与自身免疫性疾病的相关性尚不清楚.     

Th17细胞与肝脏疾病的研究进展

机体免疫系统是抵抗外来病原体和各种损害的防御系统,根据CD4^＋T细胞的功能经典地分为辅助性T细胞（Th1、Th2）、细胞毒性T细胞以及调节性T细胞（Treg）3个亚群。Th1介导细胞免疫,Th2介导体液免疫,而Treg则在维护机体免疫平衡中发挥重要作用。然而随着对自身免疫性疾病的研究,发现一群不同于Th1、Th2、Treg的新型CD4^＋T细胞亚群——Th17细胞。已证实Th17细胞与清除胞外病原体、炎症、自身免疫性疾病和肿瘤的发生发展有密切联系。随着人们对肝炎、肝纤维化和肝癌等肝病认识不断加深,这种新型的Th17细胞在这些疾病中发生发展的作用机制也不断的被研究者所关注。     

HIV／AIDS患者体内Th17及Th1应答失衡

目的 探讨HIV/AIDS患者体内Th17、Th1应答情况及Th17与Th1应答之间的相互关系.方法 选取38例符合诊断标准的慢性HIV感染患者,根据抗病毒治疗与否,将其分为2组：治疗前16例,治疗后22例,同时选取24例健康志愿者为对照.采用全血胞内细胞因子染色方法,使用BD FACSCanto流式细胞仪检测各项指标,FACSDiva软件分析CD4^＋IL-17^＋T细胞及CD4^＋IFN-γ^＋T细胞表达情况,将结果进行统计学分析并比较各组之间的差异.结果 未治疗患者CIM^＋IL-17^＋T细胞表达显著低于健康对照（1.14±0.79）%vs（3.98±1.14）%,P=0.000,经抗毒治疗后明显升高（2.22±1.00）%,P=0.001;而CD4^＋IFN-γ^＋T细胞则在治疗前后没有显著变化（34.35±24.38% vs42.10＋15.57%）,与健康人比较亦差异无统计学意义P=0.383;进一步相关性分析表明CD4^＋IL-17^＋T细胞与CD4^＋T细胞计数呈正相关（R=0.345,P=0.034）,而CD4^＋IFN-γ^＋T细胞则与CD4^＋T细胞计数没有明显相关性（R=-0.247,P=0.136）.结论 人体感染HIV病毒以后,机体出现Th17应答显著下调,Th17/Th1平衡紊乱,Th17免疫应答可能在HIV感染致病机制中起着重要作用.     

U87MG培养上清致Na觙ve CD4分化为Th2细胞的能力降低

目的肿瘤微环境或者肿瘤细胞本身对免疫细胞的分化具有定向诱导作用,本研究目的在于了解胶质瘤细胞株U87MG外泌分子对Na觙ve CD4细胞分化可能的影响。方法外周血PBMC中分离Na觙ve CD4细胞,U87MG培养液上清以1/5量加至Na觙veCD4细胞培养体系中,培养7 d,检测Na觙ve CD4细胞分化增殖情况以及分化为Th1、Th2、Th17、Treg四个亚群量的变化。结果加有1/5量U87MG培养上清的Na觙ve CD4细胞分化成Th2减低,较对照组有显著性差异8.17%±2.08%vs 9.63%±2.48%(P<0.05),Th1较对照组均值低,但无显著性差异,Th17、Treg细胞在2组之间无明显差异。结论观察到U87MG外泌分子Na觙ve CD4分化为Th2细胞能力减弱,同时初步观察了Na觙ve CD4细胞分化为其他亚群的变化规律,为理解肿瘤细胞对Na觙ve CD4细胞分化影响提供了实验基础。     

The capacity of the natural ligands for CD28 to drive IL-4 expression in naïve and antigen-primed CD4+ and CD8+ T cells

The B7/CD28 costimulatory pathway plays a critical role in T cell activation including Th1/Th2 differentiation. However, little is known about whether CD28 costimulation favors polarization of either Th1 and Th2 or both. Here, we show a critical role of the natural ligands for CD28 molecules (B7.2-Ig or B7.1-Ig fusion proteins), particularly in the induction of type 2 T cell polarization. Upon TCR-triggering with suboptimal doses of anti-CD3, costimulation of na?ve CD4+ T cells with anti-CD28 mAb or B7-Ig fusion proteins led to comparable levels of IFN-gamma production. Na?ve T cells could produce IL-4 when CD28 costimulation was done with B7-Ig, but not with anti-CD28. IL-4-selective upregulation was also observed when T cells from anti-OVA TCR transgenic mice were stimulated with OVA in the presence of B7-Ig. Correlating with IL-4 expression, GATA-3 expression was induced much more potently by costimulation with B7-Ig than with anti-CD28 mAb, while T-bet induction by these two costimulatory reagents was comparable. This B7 effect was also applied for na?ve and antigen-primed CD8+ T cells: IL-4-expressing CD8+ T cells were generated when na?ve and alloantigen-primed T cells were stimulated with anti-CD3 and recall antigens, respectively, in the presence of B7-Ig costimulation. Importantly, such CD8+ T cell differentiation required the coexistence of CD4+ T cells during the initial TCR stimulation. These observations indicate that both type 2 CD4 and CD8 T cell polarizations are efficiently induced via costimulation of CD28 with its natural ligands, although the differentiation of CD8+ T cells is dependent on CD4+ cells.     

Beta interferon restricts the inflammatory potential of CD4+ cells through the boost of the Th2 phenotype, the inhibition of Th17 response and the prevalence of naturally occurring T regulatory cells

Beta-interferon (IFN-beta) is a valuable therapy for multiple sclerosis (MS) which is also effective in the animal model of experimental autoimmune encephalomyelitis (EAE). However, the accurate mechanisms to explain its anti-inflammatory activity in the disease are not fully revealed. Available data support that T lymphocytes are among the main cell targets of IFN-beta. We have found that in vitro anti-CD3 stimulation of uncommitted murine na?ve T cells under IFN-beta treatment results in skewing the T cell differentiation process towards the T2 phenotype, in a prevention from apoptosis of naturally occurring CD4+ T regulatory cells (nTreg) in correlation with an increase in Bcl-XL expression, and in a decrease of IL-17 expression. Elimination of nTreg from the primary culture of na?ve CD4+ cells abolished the down-regulation of IL-17 driven by IFN-beta, what suggests the interaction between Th17 and nTreg subsets. Experiments in EAE induced in SJL mice, showed in vivo evidence for the accumulation of spleen CD4+CD25+GITR+Foxp3+ cells after IFN-beta treatment. On the other hand, treated animals showed a striking decrease of IL-17 expression by peripheral CD4+ cells (Th17) and MBP-specific spinal cord cells. Both the in vivo and in vitro results point out new targets through which IFN-beta could exert its therapeutic action.     

gammadelta T cells: an important source of IL-17

IL-17 is a cytokine that plays an important role in orchestrating innate immune function. In addition, IL-17 has been shown to exacerbate autoimmune diseases. CD4(+) alphabeta T cells, gammadelta T cells, and NK cells all produce IL-17. Th17 cells are a newly defined alphabeta(+) T cell lineage characterized by IL-17 production. However, gammadelta T cells are often the major source of this cytokine. Their response can be very rapid during bacterial infections and has been shown to be protective, but IL-17-producing gammadelta T cells have also been found to exacerbate collagen-induced arthritis. Interestingly, some gammadelta T cells produce IL-17 in response to IL-23 alone, even in na?ve animals, suggesting they are already differentiated and may develop differently than CD4(+) alphabeta Th17 cells.     

Interleukin-21: a critical regulator of the balance between effector and regulatory T-cell responses

Na?ve T cells can commit to effector [T helper 1 (Th1), Th2 and Th17] or regulatory lineages. Skewing of responses toward inflammatory Th1, Th2 or Th17 pathways and away from regulatory T-cell pathways might be responsible for the initiation and progress of immune-mediated diseases. Based on recent data, we propose that interleukin-21 (IL-21), a cytokine produced by activated CD4+ T cells, induces the development of Th17 cells, blocks the differentiation of transforming growth factor-beta1-induced regulatory T cells and renders CD4+ T cells resistant to the suppressive effects of regulatory T cells, thereby playing a major role in pathogenic T-cell responses.     

CD27-CD70轴与自身免疫性疾病的关系

CD27-CD70共刺激信号途径是除了经典CD28-CD80/86轴外,初始T细胞活化第二个重要的共刺激信号途径.CD70-CD27轴为T、B细胞提供刺激信号、调节其免疫应答.对CD27-CD70轴的作用及与自身免疫性疾病关系的研究,有助于更加了解自身免疫性疾病的发病机制,为免疫治疗提供新思路.     

Changes in the expression of CD31 and CXCR3 in CD4+ naïve T cells in elderly persons

So far, very few studies exist on the na?ve T cell population of elderly persons. Only recently an increase in the percentage of long lived CD4(+)CD31(-) na?ve T cells has been claimed to occur with aging. We, therefore, characterised CD31(+) and CD31(-) CD45RA(+) CD4(+) T cells in young and healthy elderly persons. The production of IL-2 and IFN-gamma by the different subpopulations was studied following stimulation with PMA and Ionomycin. The expression of CD28, CD11a, CD62L, CXCR3 and CCR7 was also analysed. The results of this study demonstrate a pronounced increase in the percentage of CD31(-) CD45RA(+) T cells within the CD4 subpopulation of elderly persons. Both, CD31(-) and CD31(+) CD45RA(+) cells expressed CD28, CD62L, were CD11a (dim) and produced IL-2 but no IFN-gamma. This phenotype confirms that they were na?ve T cells. IL-2 production by na?ve T cells was not impaired in elderly persons. Interestingly, CD31(+) as well as CD31(-) na?ve T cells contained a subpopulation of CXCR3(+) cells in elderly individuals, but not in young ones. In spite of expressing this chemokine receptor that enables the cells to migrate into inflammatory tissues, they were still CCR7(+) and CD62L(+). We speculate that due to previous contact with local environmental factors, this subset of na?ve T cells acquires a different chemokine receptor phenotype, resulting in an altered migratory capacity in old age. Aberrant contact with antigen and effector cell differentiation in unorthodox locations may be the consequence. This could also affect Th1/Th2 polarisation, which is known to be impaired in elderly persons.     

Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor

Mesenchymal stem cells (MSCs) inhibit T‐cell activation and proliferation but their effects on individual T‐cell‐effector pathways and on memory versus naïve T cells remain unclear. MSC influence on the differentiation of naïve and memory CD4⁺ T cells toward the Th17 phenotype was examined. CD4⁺ T cells exposed to Th17‐skewing conditions exhibited reduced CD25 and IL‐17A expression following MSC co‐culture. Inhibition of IL‐17A production persisted upon re‐stimulation in the absence of MSCs. These effects were attenuated when cell–cell contact was prevented. Th17 cultures from highly purified naïve‐ and memory‐phenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX‐2 inhibitor. Media from MSC/Th17 co‐cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC‐mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation‐induced IL‐17A secretion by naturally occurring, effector‐memory Th17 cells from a urinary obstruction model was also inhibited by MSC co‐culture in a COX‐dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naïve and memory T‐cell precursors and inhibit naturally‐occurring Th17 cells derived from a site of inflammation. Suppression entails cell‐contact‐dependent COX‐2 induction resulting in direct Th17 inhibition by PGE2 via EP4.     

Heterogeneity of CD4(+) and CD8(+) T cells

There is extensive plasticity in the T-cell response to antigen. Helper CD4(+) T cells, cytotoxic CD8(+) T cells, the progression from na?ve to effector and memory T cells, and differentiation into Th1, Tc1, Th2 and Tc2 subsets have long been recognized. More recently it has become apparent that T-cell populations display additional diversity in terms of phenotype, anatomical distribution and effector function.