c-Maf参与调节性T细胞特化的研究进展

调节性T细胞(regulatory T cell,Treg)在抑制免疫方面具有独特的作用,是宿主维持机体免疫稳态的主要细胞。近年来研究发现,Treg细胞可继续分化为多种亚型,在不同的组织环境和免疫应答中会适应性表现辅助性T细胞(helper T lymphocytes,Th)的特殊表型,表达与Th相关的转录因子,发挥独特的功能特性。肌腱膜纤维肉瘤原癌基因转录因子(c-musculoaponeurotic-fibrosarcoma,c-Maf)在Treg细胞的适应性分化过程有着重要作用。本文就c-Maf在Treg细胞中的特化作用做一简要综述,其中主要涉及表达核激素受体视黄酸受体相关孤儿受体γt(receptor-related orphan receptorγt,RORγt)Treg细胞和表达B细胞淋巴瘤蛋白6(B-cell lymphoma 6,Bcl-6)的滤泡调节性T细胞(follicular regulatory T cell,Tfr)的形成,以进一步讨论Treg细胞介导的免疫机制。     

Tfh与Tfr的研究进展及其在类风湿性关节炎发展中的作用

滤泡辅助性T细胞(follicular helper T cell,Tfh)和滤泡调节性T细胞(follicular regulatory T cell,Tfr)是近年新发现的两种重要的T细胞类型,它们对促进生发中心(germinal center,GC)形成、B细胞发育及高亲和抗体产生具有重要作用。类风湿性关节炎(rheumatoid arthritis,RA)是一种常见的慢性系统性自身免疫性疾病,以关节滑囊组织炎症和关节退化为主要特征,同时存在多种自身反应性抗体的异常表达。本文综述Tfh与Tfr的分化与分子标志及主要功能的研究进展,阐述两种细胞在RA发展中的可能作用。     

Tfh、Tfr细胞表达情况与HSP患儿肾脏受累情况的关系

目的 研究过敏性紫癜(Henoch Sch(o)nlein purpura,HSP)患儿外周血滤泡调节性T细胞(follicular regulatoryT cells,Tfr细胞)、滤泡辅助性T细胞(follicular helperT cells,Tfh细胞)的表达情况,及其与肾脏受累的关系.方法 选取我院2017...     

滤泡辅助性T细胞在HIV感染及疫苗免疫中的作用及机制

滤泡辅助性T细胞( follicular helper T cell, Tfh )是近期发现的具有B细胞辅助功能的CD4+T淋巴细胞亚群, 对于生发中心形成、亲和力成熟、高亲和力抗体产生和记忆B细胞的发育至关重要。Tfh与艾滋病(acquired immunodeficiency syndrome, AIDS)发展进程密切相关。在人类免疫缺陷病毒(human immunodeficiency virus, HIV)感染过程中, Tfh细胞数量、功能、病毒潜伏、Tfh/滤泡调节T细胞(follicular regulatory T cell, Tfr)比例平衡、中和抗体产生等方面均发生变化。文章综述Tfh在HIV感染及疫苗免疫后抗体应答中的作用及机制, 旨在为HIV疫苗的设计与免疫策略制定提供参考。     

滤泡辅助性T细胞和滤泡调节性T细胞与自身免疫病

自身抗体作为自身免疫性风湿病的标志已被用于临床诊断数十年,而自身抗体产生的免疫学机制直到滤泡辅助性T细胞(T follicular helper,T_(FH)cells)和滤泡调节性T细胞(T follicular regulatory,T_(FR)cells)的发现才逐渐被阐明。在生发中心反应及体液免疫记忆形成过程中,T_(FH)细胞辅助抗体的亲和力成熟,而T_(FR)细胞则抑制T_(FH)介导的抗体反应。自身免疫性风湿性疾病患者的T_(FH)细胞数量增加且功能活跃,T_(FR)细胞的数量降低且功能低下,T_(FH)细胞和T_(FR)细胞之间的平衡发生异常。因此,深入研究T_(FH)和T_(FR)细胞发育及功能的分子机制,可为疾病治疗寻找新的靶标。随着对T_(FH)和T_(FR)细胞的深入了解,基于恢复T_(FH)和T_(FR)细胞间的平衡的策略,将为风湿性疾病的预防及治疗提供新的策略。     

c-Rel转录因子对T淋巴细胞免疫调控的研究进展

<正>1 NF-κB及c-Rel概述T淋巴细胞(T细胞)是淋巴细胞的一种,在免疫反应中扮演着重要的角色。根据效应功能,T细胞可分为辅助性T细胞(help T cell,Th)、细胞毒性T细胞(Cytotoxic T cell,Tc或CTL)和调节性T细胞(regulatory T cell,Tr或Treg)等。而辅助性T细胞又可分为Th1、Th2、Th17、Th9和Tfh(follicular helper     

HIV感染者外周血Tfh细胞与B细胞异常分化相关性分析

目的:探讨HIV感染急性期(acute HIV infection, AHI)和慢性期(chronic HIV infection, CHI)外周血滤泡辅助性T细胞(circulating T follicular helper cell,cTfh)的动力学变化及对B细胞分化的影响。方法:从北京佑安医院男男性行为高危筛...     

BTLA对调节性T细胞发育及功能的影响

目的 研究B和T淋巴细胞弱化因子(B and T lymphocyte attenuator,BTLA)对调节性T细胞(regulatory T cell,Treg)发育和功能的影响.方法 构建在Treg中特异性敲除BTLA基因的小鼠模型,使用流式细胞术检测该模型小鼠中枢及外周各淋巴器官中T细胞外周环境稳态、T细胞的活...     

地塞米松体外短期处理影响Ⅰ型调节性T 细胞与自然调节性T 细胞平衡

目的:本研究拟通过地塞米松体外短期处理外周血淋巴细胞探讨地塞米松对调节性T 细胞包括自然调节性T 细胞(Natural regulatory T cell,Treg)和Ⅰ型调节性T 细胞(Type I regulatory T cell,Tr1) 的影响。方法:取健康人外周血淋巴细胞,分为地塞米松处理组和阴性对照组,处理3 d 后按多色分析法进行染色,用流式细胞仪检测并分析CD25、CD127、淋巴细胞活化因子3(Lymphocyte-activation 3,LAG-3)和叉头样转录因子3(Forkhead box P3,Foxp3)的表达及Treg 和Tr1 的频率变化。结果:相对于对照组,地塞米松处理3 d 后CD4+ T 细胞频率增加且呈剂量依赖性;CD4+ T 细胞上CD25 和Foxp3 的表达显著降低(P =0.006,P<0.000 1),而CD127 和LAG-3 表达显著升高(P<0.000 1、P =0.011);Treg 频率显著降低(P<0.001),而Tr1频率显著升高(P =0.051),且增加Tr1/ Treg 细胞比率(P =0.044)。结论:地塞米松体外短期处理上调Tr1 比率,下调Treg 比率,改变Tr1 与Treg 细胞平衡。     

Th17/Treg在早期判断狼疮性肾炎治疗反应中的应用价值

目的:了解外周血辅助性T细胞(helper T cell,Th)17 /调节性T细胞(regulatory T cells,Treg)和相关细胞因子在狼疮性肾炎(lupus nephritis,LN)治疗前后的变化和意义,并评估Th17/Treg在预测LN治疗反应中的价值。方法:选取2016年2月至2018年10月于复...     

Immunologic characteristics of HIV-infected individuals who make broadly neutralizing antibodies

Induction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV-1) is a key, as-yet-unachieved goal of prophylactic HIV-1 vaccine strategies. However, some HIV-infected individuals develop bnAbs after approximately 2-4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4⁺ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4⁺ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy-chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4⁺ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV-1 infection, in particular alterations in CD4⁺ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV-1 vaccine design.     

Disentangling Tfr cells from Treg cells and Tfh cells: How to untie the Gordian knot

T follicular regulatory (Tfr) cells are a subpopulation of Treg cells that have adopted the T follicular helper cell program to localize to the B‐cell follicle. Because of the difficulties in generating mouse models in which Tfr cells are selectively affected, determining where and how Tfr cells regulate the germinal center response remains to be resolved. In this issue of the European Journal of Immunology, Dent and colleagues [Eur. J. Immunol. 2016. 46: 1152–1161] describe a simple, elegant mouse model to conditionally delete Tfr cells without impacting on the Treg‐ and Tfh‐cell populations. Their initial studies suggest that Tfr cells have a more complex role than previously thought, particularly with respect to the regulation of immunoglobulin isotype switching to IgA.     

T follicular regulatory cells

Pathogen exposure elicits production of high-affinity antibodies stimulated by T follicular helper (Tfh) cells in the germinal center reaction. Tfh cells provide both costimulation and stimulatory cytokines to B cells to facilitate affinity maturation, class switch recombination, and plasma cell differentiation within the germinal center. Under normal circumstances, the germinal center reaction results in antibodies that precisely target foreign pathogens while limiting autoimmunity and excessive inflammation. In order to have this degree of control, the immune system ensures Tfh-mediated B-cell help is regulated locally in the germinal center. The recently identified T follicular regulatory (Tfr) cell subset can migrate to the germinal center and inhibit Tfh-mediated B-cell activation and antibody production. Although many aspects of Tfr cell biology are still unclear, recent data have begun to delineate the specialized roles of Tfr cells in controlling the germinal center reaction. Here we discuss the current understanding of Tfr-cell differentiation and function and how this knowledge is providing new insights into the dynamic regulation of germinal centers, and suggesting more efficacious vaccine strategies and ways to treat antibody-mediated diseases.     

Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice

Follicular helper T (Tfh) cells provide crucial help to germinal center B (GCB) cells for proper antibody production, and a specialized subset of regulatory T cells, follicular regulatory T (Tfr) cells, modulate this process. However, Tfr‐cell function in the GC is not well understood. Here, we define Tfr cells as a CD4⁺ Foxp3⁺ CXCR5^hi PD‐1^hi CD25^low TIGIT^high T‐cell population. Furthermore, we have used a novel mouse model (“Bcl6FC”) to delete the Bcl6 gene in Foxp3⁺ T cells and thus specifically deplete Tfr cells. Following immunization, Bcl6FC mice develop normal Tfh‐ and GCB‐cell populations. However, Bcl6FC mice produce altered antigen‐specific antibody responses, with reduced titers of IgG and significantly increased IgA. Bcl6FC mice also developed IgG antibodies with significantly decreased avidity to antigen in an HIV‐1 gp120 “prime‐boost” vaccine model. In an autoimmune lupus model, we observed strongly elevated anti‐DNA IgA titers in Bcl6FC mice. Additionally, Tfh cells from Bcl6FC mice consistently produce higher levels of Interferon‐γ, IL‐10 and IL‐21. Loss of Tfr cells therefore leads to highly abnormal Tfh‐cell and GCB‐cell responses. Overall, our study has uncovered unique regulatory roles for Tfr cells in the GC response.     

Increased circulating follicular regulatory T cells in Hashimoto’s thyroiditis

Abstract

Objective: Follicular T helper (Tfh) cells are involved in the pathogenesis of Hashimoto's thyroiditis (HT), while follicular T regulatory (Tfr) cells inhibit Tfh cells, which mediate B cell responses. However, the role of Tfr cells in HT remains unclear.

Methods: Forty-six healthy controls (HCs) and 84 HT patients were enrolled in the study. The percentage of Treg cells, CXCR5^? Treg cells, and Tfr cells; the Tfr/Tfh ratio; and the percentage of ICOS, PD-1, CTLA-4, CXCR3 and CCR6 in Tfr cells were investigated; furthermore, the associations between the percentage of Tfr cells or the Tfr/Tfh ratio and the autoantibody indices were investigated.

Results: Compared with that in the HCs, the percentage of Treg cells in the HT patients was not significantly changed, but the percentage of CXCR5^? Tfr cells was decreased. In contrast, both the percentage of Tfr cells and the Tfr/Tfh ratio were significantly increased in the HT patients. Among the Tfr cells, the percentage of Th2-like Tfr cells was increased in the HT patients, while the percentage of Th17-like Tfr cells was decreased. Moreover, the percentages of ICOS and PD-1 on Tfr cells were significantly increased in the HT patients, while the percentage of CTLA-4 on Tfr cells was significantly decreased. However, the percentage of ICOS, PD-1 and CTLA-4 on Treg or CXCR5^? Treg cells was not significantly changed. Last, no association was found between either the percentage of Tfr cells or the Tfr/Tfh ratio and the antithyroglobulin and antithyroid peroxidase antibody levels in the HT patients.

Conclusions: In the HT patients, the circulating Tfr cell percentage and Tfr/Tfh ratio were significantly increased, but the humoral immune function of Tfr cells might be impaired.     

Altered follicular regulatory T (Tfr)- and helper T (Tfh)-cell subsets are associated with autoantibody levels in microscopic polyangiitis patients

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by B cells-derived ANCAs, and ANCA was proved to be a key factor in its pathogenesis. Follicular regulatory T (Tfr) and follicular helper T (Tfh) cells were T-cell subsets that play important roles in B-cell maturation and antibody production. However, their significances in microscopic polyangiitis (MPA) patients, one type of AAV, has not been thoroughly studied. In this study, comprehensive pattern analyses of circulating Tfr and Tfh were performed in MPA patients and healthy controls (HCs), and we found Tfr levels and Tfr/Tfh ratios were significantly decreased in MPA patients. Compared with HCs, Helios+, CD45RA-FoxP3hi, and Ki-67+ Tfr were lower in MPA patients, while CD226+ Tfr cells were higher. These phenotypes suggest that function and proliferation ability of Tfr cells were relatively impaired. Tfh subsets, including ICOS+PD-1+ and Ki-67+ Tfh, were significantly increased, suggesting that the function of Tfh was enhanced in MPA although the total Tfh levels did not change significantly. Circulating memory B cells and plasmablasts were significantly elevated and negatively correlated with Tfr levels and Tfr/Tfh ratios in MPA patients. In addition, Tfr levels and Tfr/Tfh ratios were negatively while Tfh was positively correlated with serum myeloperoxidase (MPO)-ANCA levels. Furthermore, Tfr and Tfr/Tfh ratio were also reversely associated with SCr, BUN, IL-4, and IL-21 levels. Our results suggest that the imbalance of Tfr and Tfh functional subsets is related to increased level of autoantibodies in MPA patients, and we propose a new mechanism for the pathogenesis of MPA.     

Decreased circulating follicular regulatory T cells in patients with dilated cardiomyopathy

Follicular regulatory T cells (Tfr) have critical functions in inflammatory and autoimmune disorders. The main purpose of the current work was to assess Tfr cell frequency in patients with dilated cardiomyopathy (DCM). Flow cytometry showed that, compared with normal controls, DCM cases showed markedly reduced Tfr cell rates and Tfr/Tfh ratios, but significantly increased follicular helper T cell (Tfh) rates. Correlation analysis showed that the Tfr rate in DCM patients was positively correlated with left ventricular ejection fraction (LVEF), and negatively correlated with N-terminal brain natriuretic peptide (NT-proBNP) levels. Lower Foxp3 and higher Bcl-6, ICOS, and PD-1 mRNA expression levels were found in patients with DCM. In addition, plasma interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-21 levels were significantly increased in DCM cases. Moreover, IgG and IgG3 levels were also elevated in individuals with DCM. Correlation analysis showed that the Tfr rate in DCM patients was negatively correlated with IgG and IgG3, while the Tfh rate was positively correlated with IgG and IgG3. Changes in circulating Tfr levels may have a critical immunomodulatory function in DCM and may become a new therapeutic target for DCM.     

From dendritic cells to B cells dysfunctions during HIV‐1 infection: T follicular helper cells at the crossroads

T follicular helper (Tfh) cells are essential for B‐cell differentiation and the subsequent antibody responses. Their numbers and functions are altered during human and simian immunodeficiency virus (HIV/SIV) infections. In lymphoid tissues, Tfh cells are present in germinal centre, where they are the main source of replicative HIV‐1 and represent a major reservoir. Paradoxically, Tfh cell numbers are increased in chronically infected individuals. Understanding the fate of Tfh cells in the course of HIV‐1 infection is essential for the design of efficient strategies toward a protective HIV vaccine or a cure. The purpose of this review is to summarize the recent advance in our understanding of Tfh cell dynamics during HIV/SIV infection. In particular, to explore the possible causes of their expansion in lymphoid tissues by discussing the impact of HIV‐1 infection on dendritic cells, to identify the molecular players rendering Tfh cells highly susceptible to HIV‐1 infection, and to consider the contribution of regulatory follicular T cells in shaping Tfh cell functions.