T－B细胞协作研究的重大突破——滤泡辅助性T细胞的发现，一个新的CD^4＋效应T细胞亚群

二十世纪60年代,Claman和Miller等[1,2]分别采用照射或胸腺切除的小鼠模型,同时过继转移正常小鼠骨髓细胞和胸腺细胞,或过继转移胸腺细胞或胸导管淋巴细胞,才能产生针对羊红细胞抗体,发现了B细胞对某些抗原(后称为T细胞依赖抗原)刺激产生抗体必须要有T细胞的辅助.     

滤泡辅助性T细胞的主要特性及其活化的信号转导途径

滤泡辅助性T细胞能够迁移到淋巴滤泡,参与促进生发中心的形成、维持,浆细胞(长寿的和短寿的)和记忆B细胞的产生和抗体类别转换,在辅助B淋巴细胞产生抗体中起着重要作用,是近年来发现的一种新CD4+辅助性T细胞亚群。本文将重点围绕目前综述涉及不多的信号通路调控,综述滤泡辅助性T细胞的发育分化、主要特性及与疾病的关系。     

儿童持续性免疫性血小板减少性紫癜患儿滤泡辅助性T细胞改变初探北大核心CSCD

目的：探讨滤泡辅助性T细胞（ T follicular helper , Tfh）在儿童持续性免疫性血小板减少性紫癜（ persistent immune thrombocytopenic purpura , pITP ）免疫发病机制中的可能作用。方法pITP患儿20例,采用流式细胞术检测外周血循环CD4＋CXCR5＋ICOShigh PD-1high T （ cTfh）细胞比例及CD19＋B细胞ICOSL（inducible co-stimulator ligand）的表达,采用实时荧光定量PCR（real-time PCR）检测Bcl-6、c-Maf、IL-21 mRNA及CD19＋B细胞ICOSL mRNA表达,酶联免疫吸附试验检测血浆IL-2、IL-6、IL-21浓度。结果（1）pITP患儿cTfh细胞比例明显高于正常对照组[（17．45±9．04）％ vs （7．57±2．57）％, P＜0．05],地塞米松（DEX）治疗7 d后cTfh细胞比例明显低于治疗前[（5．93±1．64）％vs （17．45±9．04）％,P＜0．05];（2）Tfh细胞转录调节因子Bcl-6及c-Maf表达较正常对照组明显增高（P＜0．05）;（3）pITP患儿CD19＋B细胞ICOSL蛋白和基因表达明显增高（P＜0．05）,DEX治疗后CD19＋B细胞ICOSL表达与治疗前相比无明显改变（P＞0．05）;（4）Tfh细胞相关细胞因子IL-21血浓度和基因表达水平明显高于正常对照组（P＜0．05）,DEX 治疗后仍显著高于对照组（P＜0．05）,IL-2及IL-6血浆浓度治疗前后与正常对照组相比无明显改变（P＞0．05）。结论 ICOSL和IL-21表达异常所致Tfh细胞过度活化可能与pITP患儿免疫发病机制有关;B细胞持续高表达ICOSL和IL-21持续高水平可能是导致pITP患儿病情反复发作的原因之一。     

滤泡辅助性T细胞与相关疾病研究进展

滤泡辅助性T细胞(Tfh)是近几年发现的一种新的T细胞亚群,与Th1细胞、Th2细胞、Th17细胞及调节性T细胞(Tr)相互促进或拮抗,维持免疫系统的正常生理功能,其主要功能是辅助B细胞分化、发育和促进体液免疫应答,当Tfh细胞数量或功能紊乱时可引起自身免疫病、免疫缺陷病、肿瘤或感染性疾病的发生或加重.     

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。     

IL-21在滤泡辅助性T细胞分化发育及功能中的作用

抗原刺激B细胞产生抗体需要T细胞辅助,近年来人们逐渐认识到一个命名为滤泡辅助性T细胞(Tfh)的CD4+T细胞亚群在B细胞诱导的免疫应答中具有重要作用.Tfh细胞的主要特征包括表达趋化因子受体与(CXCR5),迁移定位于B细胞滤泡辅助B细胞产生抗体.Tfh细胞产生的细胞因子IL-21能够促进B细胞分化为抗体形成细胞,这种辅助性细胞因子在Tfh细胞的分化发育、效应发挥及Tfh细胞功能失调相关的疾病中具有重要意义.     

实验性免疫性不育雄性小鼠滤泡辅助性T细胞相关细胞因子水平分析

目的:检测实验性免疫性不育小鼠滤泡辅助性T(Tfh)细胞相关细胞因子IL-4、IL-12、IL-17、IL-21水平,探讨滤泡辅助性T细胞在免疫性不育发病中的作用.方法:采用同种小鼠精子及完全弗氏佐剂免疫BALB/c雄性小鼠,获得免疫性不育动物模型,同时设立正常对照组给予0.9％的生理盐水.流式细胞术检测免疫性不育小鼠...     

急性期川崎病患儿滤泡辅助性T细胞改变观察

目的 探讨滤泡辅助性T细胞(Tfh细胞)在儿童川崎病(Kawasaki disease,KD)中的数量变化及其可能机制.方法 急性期川崎病患儿20例,采用流式细胞术检测外周血CD4+CXCR5+ICOS+T细胞(Tfh)的比例,采用real-time PCR检测转录调节因子Bcl-6、Blimp-1 mRNA表达,酶联免疫吸附试验检测血浆中IL-4和IL-21浓度;20例同龄健康儿童作为对照组.结果 (1)急性期KD患儿Tfh细胞比例明显高于正常对照组[(2.6±0.6)％vs(1.8±0.7)％,P＜0.05];(2)Tfh细胞转录因子Bcl-6 mRNA表达较正常对照组明显增高(P＜0.05),其拮抗因子Blimp-1 mRNA表达降低(P＜0.05);(3)血浆IL-21和IL-4蛋白浓度明显高于正常对照组(P＜0.05).结论 Tfh细胞过度活化可能参与了KD免疫发病机制,Bcl-6/Blimp-1表达失衡,IL-4和IL-21细胞因子微环境改变可能与Tfh细胞异常活化有关.     

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.     

IL-21在滤泡辅助性T细胞分化发育及功能中的作用

抗原刺激B细胞产生抗体需要T细胞辅助,近年来人们逐渐认识到一个命名为滤泡辅助性T细胞（Tfh）的CD4^＋T细胞亚群在B细胞诱导的免疫应答中具有重要作用。Tfh细胞的主要特征包括表达趋化因子受体与（CXCR5）,迁移定位于B细胞滤泡辅助B细胞产生抗体。Tfh细胞产生的细胞因子IL-21能够促进B细胞分化为抗体形成细胞,这种辅助性细胞因子在Tfh细胞的分化发育、效应发挥及Tfh细胞功能失调相关的疾病中具有重要意义。     

Blood relatives of follicular helper T cells

Deliberate redirection of T?cell responses to human immunodeficiency virus-1 might enhance immunity and thus aid viral containment. Dahirel et?al. (2011) identify candidate antigens to achieve this with a theory derived from physics.     

The potential role of follicular helper T cells in idiopathic multicentric Castleman disease with and without TAFRO syndrome

Idiopathic multicentric Castleman disease (iMCD) is a systemic inflammatory disease of unknown etiology caused by hypercytokinemia. Recently, TAFRO (thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly) syndrome has been reported, which shows similar histopathological findings to iMCD and factors associated with a poor prognosis. iMCD shows no plasma cell infiltration in the germinal center (GC), but CD38-positive (CD38⁺)-plasma cells are observed in the interfollicular area. Our previous report revealed that atrophic change of GC, glomeruloid vascular proliferation, and abnormal proliferation of follicular dendritic cells are more prominent in iMCD with TAFRO (TAFRO⁺) in comparison to iMCD without TAFRO (TAFRO⁻). In addition, the numbers of CD38⁺ and immunoglobulin G4-positive (IgG4⁺) plasma cells were decreased in the interfollicular area. The roles of T follicular helper cells (Tfh) are well-known to assist B-cell proliferation, maturation, and differentiation．It maintains the formation of GC and is also related in the class switching of IgG isotypes, including IgG4. Thus, we immunohistochemically examined the number of Tfh in GCs in both TAFRO⁻ and TAFRO⁺ iMCD. The number of Tfh was significantly decreased in TAFRO⁻ iMCD (n = 9) and was further decreased in TAFRO⁺ iMCD (n = 18) in comparison to non-specific lymphadenopathy (n = 6) and IgG4-related disease (n = 4). These results suggest that decreased Tfh may be one etiology of iMCD.     

Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases

The interactions of CD4⁺ T cells and B cells are fundamental for the generation of protective antibody responses, as well as for the development of harmful autoimmune diseases. Recent studies of human tissues and blood samples have established a new subset of CD4⁺ B helper T cells named peripheral helper T (Tph) cells. Unlike T follicular helper (Tfh) cells, which interact with B cells within lymphoid organs, Tph cells provide help to B cells within inflamed tissues. Tph cells share many B helper-associated functions with Tfh cells and induce B cell differentiation toward antibody-producing cells. The differentiation mechanism is also partly shared between Tph and Tfh cells in humans, and both Tfh and Tph cells can be found within the same tissues, including cancer tissues. However, Tph cells display features distinct from those of Tfh cells, such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bcl-6/Blimp1 ratio. Unlike that of Tfh cells, current evidence shows that the target of Tph cells is limited to memory B cells. In this review, we first summarize recent findings on human Tph cells and discuss how Tph and Tfh cells play shared and distinct roles in human diseases.     

Increased CD4+CXCR5+T follicular helper cells in diabetic nephropathy

Background: T follicular helper (Tfh) cells are known to regulate humoral immune response. In this study we examined the correlation of different subsets of peripheral blood Tfh cells in patients with diabetic nephropathy (DN). Methods: A total of 23 DN patients and 15 healthy controls (HC) were investigated for various subsets of Tfh cells by flow cytometry. The molecules ICOS⁺, PD-1⁺, CD28⁺, CD154⁺, IL-21⁺, IFN-γ⁺, IL-4⁺, IL-17⁺ Tfh cells were examined. The subsets of B cells were investigated by flow cytometry. The levels of 24?h urinary protein and estimated glomerular filtration rate (eGFR) were calculated. A potential correlation between the number of different subsets of Tfh cells, B cells and DN, was assessed. Results: The circulating CD4⁺CXCR5⁺PD-1⁺, PD-1⁺CD154⁺, PD-1⁺CD28⁺, PD-1⁺IL-21⁺, PD-1⁺IL-4⁺, PD-1⁺-IL-17⁺-Tfh cell counts, CD38⁺CD19⁺, CD38⁺CD19⁺CD40⁺ B cells and plasma levels of IL-21 were significantly increased in DN patients (p?+CXCR5⁺PD-1⁺ Tfh cell counts negatively correlated with eGFR; Tfh cell counts positively correlated with 24?h urinary protein concentration in DN patients. Post-treatment, there was a significant reduction in the CD4⁺CXCR5⁺PD-1⁺ Tfh cell counts and its subsets, with a corresponding decrease in plasma levels of IL-6 and IL-17A (p?Conclusion: An increased number of CD4⁺CXCR5⁺PD-1⁺ Tfh cells were observed in DN patients, which may be new targets for intervention in DN.     

Understanding the development and function of T follicular helper cells

A fundamental function of T helper (Th) cells is to regulate B-cell proliferation and immunoglobulin class switching, especially in the germinal centers. Th1 and Th2 lineages of CD4⁺ T cells have long been considered to play an essential role in helping B cells by promoting the production immunoglobulin G2a (IgG2a) and IgG1/IgE, respectively. Recently, it has become clear that a subset CD4⁺ T cells, named T follicular helper (Tfh) cells, is critical to B-cell response induction. In this review, we summarize the latest advances in our understanding of the regulation of Tfh cell differentiation, the relationship of Tfh cells to other CD4⁺ T-cell lineages, and the role of Tfh cells in health and disease.     

Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy

Allergic diseases are characterized by overactive type 2 immune responses to allergens and immunoglobulin E (IgE)-mediated hypersensitivity. Emerging evidence suggests that follicular helper T (T_FH) cells, rather than type 2 T-helper (T_H2) cells, play a crucial role in controlling IgE production. However, follicular regulatory T (T_FR) cells, a specialized subset of regulatory T (T_REG) cells resident in B-cell follicles, restricts T_FH cell-mediated help in extrafollicular antibody production, germinal center (GC) formation, immunoglobulin affinity maturation, and long-lived, high-affinity plasma and memory B-cell differentiation. In mouse models of allergic asthma and food allergy, CXCR5⁺ T_FH cells, not CXCR5⁻ conventional T_H2 cells, are needed to support IgE production, otherwise exacerbated by CXCR5⁺ T_FR cell deletion. Upregulation of T_FH cell activities, including a skewing toward type 2 T_FH (T_FH2) and IL-13 producing T_FH (T_FH13) phenotypes, and defects in T_FR cells have been identified in patients with allergic diseases. Allergen immunotherapy (AIT) reinstates the balance between T_FH and T_FR cells in patients with allergic diseases, resulting in clinical benefits. Collectively, further understanding of T_FH and T_FR cells and their role in the immunopathogenesis of allergic diseases creates opportunities to develop novel therapeutic approaches.