外周血循环滤泡辅助性T 细胞及IL-21 在银屑病中的表达及意义

目的:探讨外周血循环滤泡辅助性T 细胞(Follicular helper T cells,Tfh)及相关细胞因子IL-21 在银屑病患者中的表达水平及其与疾病活动度的关系。方法:收集38 例银屑病患者及32 例健康对照者,流式细胞术检测外周血循环CD4+CXCR5+ Tfh 和CD4+ CXCR5+ ICOS+ Tfh 细胞比例以及Th17 细胞比例;ELISA 检测血清IL-21 浓度;分析这些指标间及与银屑病疾病活动度评分PASI 间的相关性。结果:与健康对照者相比,银屑病患者外周血循环CD4+ CXCR5+ Tfh 和CD4+ CXCR5+ ICOS+Tfh 细胞比例更高,血清IL-21 浓度和Th17 细胞比例亦显著高于对照组(P<0.05);IL-21 浓度与CD4+ CXCR5+ Tfh 和CD4+CXCR5+ ICOS+ Tfh 细胞比例均显著正相关,而与Th17 细胞比例间无显著相关性(P>0.05);且CD4+ CXCR5+ ICOS+ Tfh 细胞比例和血清IL-21 与银屑病疾病活动度PASI 评分显著正相关,而CD4+ CXCR5+ Tfh 则与之无显著相关性(P>0.05)。结论:银屑病患者外周血循环Tfh 比例、IL-21 浓度上调与银屑病患者疾病活动度密切相关,提示Tfh 可能参与银屑病的发生发展过程,这一效应可能是通过分泌高水平IL-21 实现;IL-21 浓度与Tfh 细胞比例相关,而与Th17 细胞比例无相关性提示银屑病患者IL-21可能主要由Tfh 细胞分泌。     

Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V

Follicular helper T cells (Tfh cells) are the major producers of interleukin-4 (IL-4) in secondary lymphoid organs where humoral immune responses develop. Il4 regulation in Tfh cells appears distinct from the classical T helper 2 (Th2) cell pathway, but the underlying molecular mechanisms remain largely unknown. We found that hypersensitivity site V (HS V; also known as CNS2), a 3' enhancer in the Il4 locus, is essential for IL-4 production by Tfh cells. Mice lacking HS V display marked defects in type 2 humoral immune responses, as evidenced by abrogated IgE and sharply reduced IgG1 production in vivo. In contrast, effector Th2 cells that are involved in tissue responses were far less dependent on HS V. HS V facilitated removal of repressive chromatin marks during Th2 and Tfh cell differentiation and increased accessibility of the Il4 promoter. Thus, Tfh and Th2 cells utilize distinct but overlapping molecular mechanisms to regulate Il4, a finding with important implications for understanding the molecular basis of allergic diseases.     

滤泡辅助性T细胞的研究进展

滤泡辅助性T细胞（Tfh）是最近发现的CD4^＋辅助性T淋巴细胞亚群,其作用是辅助B细胞的抗体产生.其发生、分化和功能均独立于以往的Th1、Th2和Th17细胞,是体液免疫反应的关键.转录因子Bcl-6和Blimp-1在Tfh细胞的分化中起着关键的、相互拮抗的作用,调节趋化因子受体、表面分子和细胞因子等表达,这些因子对Tfh细胞募集和B细胞辅助功能非常重要.     

A fundamental role for interleukin-21 in the generation of T follicular helper cells

T cell help to B cells is a fundamental property of adaptive immunity, yet only recently have many of the cellular and molecular mechanisms of T cell help emerged. T follicular helper (Tfh) cells are the CD4(+) T helper cells that provide cognate help to B cells for high-affinity antibody production in germinal centers (GC). Tfh cells produce interleukin-21 (IL-21), and we show that IL-21 was necessary for GC formation. However, the central role of IL-21 in GC formation reflected its effects on Tfh cell generation rather than on B cells. Expression of the inducible costimulator (ICOS) was necessary for optimal production of IL-21, indicative of interplay between these two Tfh cell-expressed molecules. Finally, we demonstrate that IL-21's costimulatory capacity for T helper cell differentiation operated at the level of the T cell receptor signalosome through Vav1, a signaling molecule that controls T cell helper function. This study reveals a previously unappreciated role for Tfh cells in the formation of the GC and isotype switching through a CD4(+) T cell-intrinsic requirement for IL-21.     

The role of the T follicular helper cells in allergic disease

T follicular helper (Tfh) cells were discovered just over a decade ago as germinal centre T cells that help B cells make antibodies. Included in this role is affinity maturation and isotype switching. It is here that their functions become less clear. Tfh cells principally produce IL-21 which inhibits class switching to IgE. Recent studies have questioned whether the germinal centre is the main site of IgE class switching or IgE affinity maturation. In this review, I will examine the evidence that these cells are responsible for regulating IgE class switching and the relationship between Tfh cells and T helper 2 (Th2) effector cells.     

Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation

T follicular helper (Tfh) cells promote T?cell-dependent humoral immune responses by providing T?cell help to B cells and by promoting germinal center (GC) formation and long-lived antibody responses. However, the cellular and molecular mechanisms that control Tfh cell differentiation in?vivo are incompletely understood. Here we show that interleukin-2 (IL-2) administration impaired influenza-specific GCs, long-lived IgG responses, and Tfh cells. IL-2 did not directly inhibit GC formation, but instead suppressed the differentiation of Tfh cells, thereby hindering the maintenance of influenza-specific GC B cells. Our data demonstrate that IL-2 is a critical factor that regulates successful Tfh and B cell responses in?vivo and regulates Tfh cell development.     

Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion

Although a fraction of human blood memory CD4(+) T cells expresses chemokine (C-X-C motif) receptor 5 (CXCR5), their relationship to T follicular helper (Tfh) cells is not well established. Here we show that human blood CXCR5(+)CD4(+) T cells share functional properties with Tfh cells and appear to represent their circulating memory compartment. Blood CXCR5(+)CD4(+) T cells comprised three subsets: T helper 1 (Th1), Th2, and Th17 cells. Th2 and Th17 cells within CXCR5(+), but not within CXCR5(-), compartment efficiently induced naive B cells to produce immunoglobulins via interleukin-21 (IL-21). In contrast, Th1 cells from both CXCR5(+) and CXCR5(-) compartments lacked the capacity to help B cells. Patients with juvenile dermatomyositis, a systemic autoimmune disease, displayed a profound skewing of blood CXCR5(+) Th cell subsets toward Th2 and Th17 cells. Importantly, the skewing of subsets correlated with disease activity and frequency of blood plasmablasts. Collectively, our study suggests that an altered balance of Tfh cell subsets contributes to human autoimmunity.     

Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4(+) cell properties during viral infection

CD4(+) T?cells differentiate into multiple effector types, but it is unclear how they form memory T?cells during infection in?vivo. Profiling virus-specific CD4(+) T?cells revealed that effector cells with T helper 1 (Th1) or T follicular helper (Tfh) cell characteristics differentiated into memory cells, although expression of Tfh cell markers declined over time. In contrast to virus-specific effector CD8(+) T?cells, increased IL-7R expression was not a reliable marker of CD4(+) memory precursor cells. However, decreased Ly6C and T-bet (Tbx21) expression distinguished a subset of Th1 cells that displayed greater longevity and proliferative responses to secondary infection. Moreover, the gene expression profile of Ly6C(lo)T-bet(int) Th1 effector cells was virtually identical to mature memory CD4(+) T?cells, indicating early maturation of memory CD4(+) T?cell features in this subset during acute viral infection. This study provides a framework for memory CD4(+) T?cell development after acute viral infection.     

Expression of human pim family genes is selectively up-regulated by cytokines promoting T helper type 1, but not T helper type 2, cell differentiation

Cytokines are the most important inducers of T helper (Th) cell differentiation. Interleukin-12 (IL-12) and interferon-alpha (IFN-alpha) are responsible for human Th1-cell differentiation, while IL-4 is the critical cytokine promoting Th2-cell development. These two subsets of cells co-ordinate immunological responses to pathogens as well as autoimmune or allergic reactions. The pim family of proto-oncogenes encodes serine/threonine-specific kinases involved in cytokine-mediated signalling pathways in haematopoietic cells. Here we demonstrate that expression of pim-1 and pim-2 mRNAs is selectively up- or down-regulated in human cord-blood-derived CD4+ cells freshly induced to polarize towards Th1 or Th2 cells, respectively, whereas their expression is inhibited in both cell types by the immunosuppressive transforming growth factor beta (TGF-beta). Moreover, the Th1-specific cytokines IL-12 and IFN-alpha, but not the Th2-specific cytokine IL-4, transiently up-regulate pim-1 and pim-2 mRNA expression in human peripheral blood T cells and natural killer cells. In addition, the Pim-1 protein levels are strongly up-regulated by Th1-specific cytokines in all of these cell types. Taken together, our results suggest that pim genes and their protein products are involved in the early differentiation process of T helper cells.     

滤泡型辅助性T淋巴细胞与慢性乙型肝炎

滤泡型辅助性T淋巴细胞是一类新的效应性CD4+T细胞亚型,分布于淋巴滤泡GC内,其分化需要BCL-6的介导,对免疫球蛋的形成至关重要。幼稚Tfh细胞可以分泌大量的IL-21,后者作为自分泌生长因子促进自身的功能活动。由于Tfh细胞及其分泌的IL-21参与B细胞的分化,成熟,以及抗体的型别转换,因此,进一步研究Tfh与IL-21的功能及其调控机制在慢性乙型乙肝血清学转换中的作用是具有重要意义的。     

Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells

Follicular T helper (Tfh) cells provide critical help to B cells for germinal center (GC) formation. Mutations affecting SLAM-associated protein (SAP) prevent GC formation because of defective T?cell-B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in?vitro differentiation of functionally competent "Tfh-like" cells that expressed interleukin-21, Tfh cell markers, and Bcl6 and rescued GC formation in SAP-deficient hosts better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wild-type, yet failed to support GCs in?vivo. Interestingly, both Tfh-like and in?vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, Th1, Th2, and Th17 cells could be reprogrammed to obtain Tfh cell characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3, and Rorc in Tfh-like and ex?vivo Tfh cells and on Bcl6 in non-Tfh cells, supporting the concept of plasticity between Tfh and other Th cell populations.     

Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sjögren's syndrome

Follicular helper T cells (Tfh), which play a pivotal role in B cell activation and differentiation in lymphoid structures, secrete IL-21 whose augmented secretion is a hallmark of several autoimmune diseases. To decipher the cellular and molecular interactions occurring in salivary glands of patients suffering from primary Sjögren's syndrome (pSS), we investigated whether salivary gland epithelial cells (SGECs) were capable to induce Tfh differentiation. Co-cultures of naïve CD4⁺ T cells and SGECs from both patients with pSS and controls were performed. Here, we report that IL-6 and ICOSL expression by SGECs contributes to naïve CD4⁺ T differentiation into Tfh cells, as evidenced by their acquisition of a specific phenotype, characterized by Bcl-6, ICOS and CXCR5 expression and IL-21 secretion, but also but by their main functional feature: the capacity to enhance B lymphocytes survival. We demonstrated an increase of serum IL-21 with systemic activity. Finally, we analyzed the potential occurrence of a genetic association between IL-21 or IL-21R gene polymorphisms and pSS or elevated IL-21 secretion. This study, which demonstrates a direct induction of Tfh differentiation by SGECs, emphasizes a yet unknown pathogenic role of SGECs and suggests that Tfh and IL-21 might be relevant biomarkers and/or therapeutic targets in primary Sjögren's syndrome.     

滤泡辅助性T细胞的分化及其与免疫性疾病的关系

初始B细胞迁移至外周淋巴器官后发生一系列的变化,其参与体液免疫应答的过程需要滤泡辅助性T细胞（Tfh）的辅助.Tfh是一类以高水平表达CXCR5为特征的T细胞亚群,其分化除了由转录因子Bcl-6调控外尚有多种因素参与,如IL-21、ICOS、T-B细胞间接触、抗体亲和力等.Tfh细胞在体内正常的免疫应答中起着重要作用,一旦其相关因子表达发生异常,将导致机体免疫功能紊乱,引发多种免疫性疾病和肿瘤.