免疫细胞

Tfh(滤泡性辅助性T细胞)

滤泡辅助性T细胞是近年来在研究中发现的一种比较特殊的辅助性T细胞（Th细胞）。有明显区别于其他Th细胞亚群的特征性标志，但是其中最主要的标志物是CXCR5+。

Tfh细胞是最近几年研究发现的一类细胞。Tfh细胞通过基因调控或者分泌细胞因子来对Ｂ细胞进行调控，间接调控体液免疫来影响人体。Tfh细胞对许多疾病都有影响，几乎每一种自身免疫病都与Tfh有着联系。【王俊文,官杰.Tfh细胞与临床疾病的研究进展.2014,35(15)】

Tfh细胞主要的功能是通过产生IL-21，辅助B细胞产生抗体而间接参与适应免疫应答，从而对机体起到保护作用。

Tfh细胞的分化

2.1 Tfh细胞分化是不同于Th1、Th2和Th17的独立的分化过程。

2.2 IL-21是Tfh细胞分化所必需的细胞因子。

IL-21在淋巴细胞活化、维持、分化及体液免疫中发挥着十分重要的作用，它能促进IFN-1的产生、增强CD8+T细胞和NK细胞的细胞毒作用。

Tfh辅助B细胞的作用机制

Tfh对B细胞介导的体液免疫应答的作用是通过其分泌或表达的多种分子实现的。IL．2l 不但在Tfh分化、发育过程中发挥重要作用，在对Tfh对B细胞的促进作用方面也起到了重要作用。研究表明，IL-21可以诱导人类扁桃体、脾脏、派氏集合区等部位分离出来的所有成熟B细胞产生大量的IgM、IgG和IgA，其机制在于IL-21诱导B细胞发生类型转换重组、浆细胞分化及Ig的分泌013]。ICOS是CD28家族中的一员，其受体(ICOS ligand，ICOSL)主要表达于包括B细胞在内的APC。ICOS．调节B细胞的功能主要是通过促进Tfh产生多种细胞因子实现的，B细胞上高表达的ICOSL与Tfh上的ICOS结合后可以诱导Bcl-6的表达，从而促进Tfh的分化、增殖，使Tfh产生更多的IL-21、IL-4、IL一10等，增强B细胞的免疫应答反应。

【周建伟,孔翠.滤泡辅助性T细胞与相关疾病研究进展.2012,9(5)】

Tfh的功能

T细胞辅助B细胞产生抗体是胸腺依赖性体液免疫反应的基本方式，也是生发中心的产生、记忆B细胞和浆细胞生成的基本要素。国外多项研究显示：Tfh在B细胞分化过程中起主要作用，它促使GC中具有抗原高亲和力，缺乏自身反应性的B细胞分化为高亲和力的浆细胞和对感染起长期保护作用的记忆性B细胞，并且在促进GC的形成和免疫球蛋白类别转换，维持长时间的体液免疫应答等方面也发挥关键作用，认为Tfh是抗体免疫应答真正的辅助者.

【辛宁，张勇，沈霞滤.泡辅助性T细胞与自身免疫性疾病的研究进展2013，1（1）】

3.1 Tfh与自身免疫病

(类风湿性关节炎、系统性红斑狼疮、原发性干燥综合征、儿童皮肌炎、重症肌无力)

在抗体介导的自身免疫病中，发挥着正向调控的作用，为自身反应性B细胞提供辅助信号，促使疾病的发生。

3.2 Tfh细胞与艾滋病

HIV病毒主要侵犯人体的CD4+T细胞导致机体的免疫力下降。Tfh是主要的抗病毒细胞，

参与了机体对病毒的杀伤和清除，研究表明Tfh细胞的生发中心HIV（HIV-1）复制更活跃。Tfh细胞AIDS患者或隐性感染者体内都是明显升高的，患者中提取出来的Tfh细胞的Bcl-6的表达也是升高的。

3．3 Tfh细胞与肝病

（自身免疫性肝炎、HBV、HCV）

Tfh细胞稳定表达CXCR5，使Tth和B细胞共同定位于淋巴滤泡，并相互作用活化B细胞，促进生发中心的形成。T f h 细胞及其相关分子( ICO S 、I L - 2 1 、C X C R 5 、P D.1 等) 可能参与肝脏疾病的免疫应答。

3.4 与肿瘤

生发中心(Germinal center，GC)：激活的B细胞因为发生了B-FDC间的相互作用，一些激活后的B细胞分化为产生IgM的浆细胞(Plasma cell)，而大部分激活的B细胞则返回到初级淋巴滤泡，并在该处大量增殖和分化，形成一种特殊的结构称为生发中心。因此,Tfh细胞对于B细胞完成的体液免疫功能发挥重要的作用。

滤泡树突状细胞(follicle dendritic cell，FDC)

FDC：位于淋巴结及脾脏滤泡中的树突状细胞。具有长的突起，可与B细胞紧密接触，表达Fc受体，但不介导内吞作用，从而使抗原-抗体复合物在其树突上形成免疫复合物包被小体而长期保存，在激活B细胞中起重要作用，可能参与B细胞的免疫记忆应答。

Tfh细胞的来源有三种模型：第一种认为Tfh细胞与Th细胞来自于不同的CD+T细胞，CD+T 细胞膜上的TCR与抗原亲和力最强的细胞分化为Tfh细胞，即前抗原模型；第二种认为Tfh 细胞与Th细胞来源一样都来源于Th细胞的前体，即多向性模型；第三种认为Tfh细胞以及其他Th细胞的分化都依靠细胞因子，并且认为Th1与Th2细胞来源于一样CD+T细胞前体，因为它们都可以产生IL-4，即协调性模型。

Central Memory CD4+ T Cells Are Responsible for the Recombinant Bacillus Calmette-Guerin [DELTA]ureC: hly V accine's Superior Protection Against Tuberculosis.中央内存CD4 + T细胞负责重组卡介苗[DELTA]ureC:他疫苗AgainstTuberculosis卓越的保护。

preclinical and clinical safety and immunogenicity. We pursue in-depth analysis of the endogenous mycobacteria-specific CD4+

T-cell population, comparing the more efficacious rBCG with canonical BCG to determine which T-cell memory responses are prerequisites for superior protection against tuberculosis. rBCG induced higher numbers and proportions of antigen-specific memory CD4+ T cells than BCG, with a CXCR5+CCR7+ phenotype and low expression of the effector transcription factors T-bet and Bcl-6. We found that the superior protection of rBCG, compared with BCG, correlated with higher proportions and numbers of these central memory T cells and of T follicular helper cells associated with specific antibody responses. Adoptive transfer of

mycobacteria-specific central memory T cells validated their critical role in protection against pulmonary tuberculosis. (C) Copyright Oxford University Press 2014.

卡介苗(BCG)已被用于结核病疫苗近一个世纪。在这里,我们分析现场结核病候选疫苗引起的免疫力,重组

BCG[DELTA]ureC:他疫苗(rBCG),证明临床前和临床安全性和免疫原性。我们追求深度分析内生

mycobacteria-specific CD4 + t细胞数量,对比更有效的与规范BCG rBCG确定哪些记忆t细胞反应的先决条

件优越的预防结核病。rBCG诱导更高的特异性记忆数字和比例比BCG CD4 + T细胞,与CXCR5 +其+表型

和低表达的效应器转录因子T-bet Bcl-6。我们发现rBCG优越的保护,与波士顿咨询公司相比,与更高的比例

和数量的这些中央记忆T细胞和卵泡辅助细胞与特定的抗体应答反应相关联。过继转移

mycobacteria-specific中央记忆T细胞验证防止肺结核的重要作用。【与是否打疫苗联系起来】

Decreased Frequencies of Circulating CD4+ TFH Cells Associated with Diminished Plasma IL-21

in Active Pulmonary Tuberculosis

低频的CD4 + Tfh细胞与活动性肺结核中血浆IL-21减少的关联性研究

Abstract

Background: Tfh cells represent a distinct subset of CD4+ T cells and are important in immunity

to infections. Although they have been shown to play a role in experimental models of

tuberculosis infection,their role in human tuberculosis remains unexplored.背景: Tfh细胞代表CD4

+ T细胞不同子集，以及和免疫感染的重要性。虽然在肺结核感染中，他们已被证明在实验模型中发挥作

用的,但他们的角色在人类结核病仍然是未知的。

Method: To determine the distribution of circulating Tfh cells in human TB, we measured the

frequencies of Tfh cells ex vivo （体外培养）and following TB - antigen or polyclonal stimulation

in pulmonary TB (PTB; n = 30) and latent TB (LTB; n = 20) individuals, using the markers

CXCR5, PD-1 and ICOS.方法:确定Tfh细胞在人类结核病的分布,测量了Tfh细胞体外培养的频率，以及

结核病——抗原或多克隆刺激后的肺结核(PTB;n = 30)和潜在的结核病(LTB;n = 20),使用CXCR5、PD-1、

ICOS进行标记。

Results: We found that both ex vivo and TB—antigen induced frequencies of Tfh cell subsets was

significantly lower in PTB compared to L TB individuals. Similarly, antigen induced frequencies

of Tfh cells expressing IL-21 was also significantly lower in PTB individuals and this was

reflected in diminished circulating levels of IL-21 and IFNc. This was not accompanied by

diminished frequencies of activated or memory B cell subsets. Finally, the diminution in

frequency of Tfh cells in PTB individuals was dependent on IL-10, CTLA-4 and PD-L1 in vitro.

我们发现体外培养和人类的肺结核病中：与人类感染LTB相比，抗原诱导的Tfh细胞频率，显著低于PTB。

同样,PTB中：抗原诱导的Tfh细胞在表达IL-21的频率也显著降低,这反映了Tfh细胞在表达IL-21和IFNc

水平均有所降低。因此，要了解PTB中Tfh细胞的降低频率，依赖于体外培养中IL-10, CTLA-4和PD-L1

的表达。

？Conclusions:Thus, PTB is characterized by a diminution in the frequency of Tfh cell subsets。

结论：PTB有一个Tfh细胞子集中的发生频率降低子的特点

Introduction

Exposure to Mycobacterium tuberculosis(Mtb) can result in a variety of outcomes, including

the absence of any clinical or laboratory evidence of infection, latent infection without active disease, active pulmonary disease or active extra-pulmonary disease [1]. 暴露在结核分枝杆菌(Mtb)

可以导致不同的结果,包括没有任何临床或实验室感染的证据,没有活动性疾病潜伏性感染,活动性肺结核疾

病或活跃的肺外疾病Although 2 billion people worldwide are infected with Mtb, only 5–10% of these individuals develop active disease, and the mechanisms by which most individuals resist development of active disease are still not clear [1].尽管全球20亿人结核分枝杆菌感染,只有5 - 10%

的这些个体发展为活动性疾病,大多数人抵抗的机制发展活动性疾病仍然不清楚However, while by definition,individuals developing active TB exhibit a compromise in their ability to mount a protective immune response against MTB, the exact nature of this protective immune response needs to be determined. A wide range of specific and non-specific host immune responses are thought to contribute to the differential outcomes of infection and disease, although there is no unifying hypothesis to explain the differences seen.然而,尽管根据定义,个人发展中活动性结核病展览妥协他们的能力对MTB保护性免疫反应,这种保护性免疫反应的确切性质需要确定。广泛的特异性和非特

异性宿主免疫反应被认为有助于鉴别感染和疾病的结果,虽然没有统一的假说来解释的差异。

Circulating Tfh cells are peripheral counterparts of conventional Tfh cells, that are predominantly located in secondary lymphoid tissues. Conventional Tfh cells are CD4+T cells that express the chemokine receptor CXCR5, co-stimulatory molecules such as ICOS, PD-1, the transcription factor Bcl-6 and the cytokine, IL-21. Circulating Tfh cells similarly express CXCR5, PD-1, ICOS but do not express Bcl-6. 循环Tfh细胞是传统Tfh细胞末梢区域的对应物，主要位于次

级淋巴组织。传统Tfh细胞即CD4 + T细胞，是表达趋化因子受体：CXCR5, 协同刺激分子，如ICOS、PD-1、转录因子Bcl-6和细胞因子IL-21。循环Tfh细胞同样表达CXCR5,PD-1,ICOS,但不表达Bcl-6。In addition,although some studies have defined circulating human Tfh cells as all CD4+ T cells expressing CXCR5 + only, other studies have suggested that CD4 + CXCR5 + T cells can be further divided into those that are PD-1+, ICOS+, and/or IL-21+. It is unclear whether expression

of PD1, ICOS or IL-21 defines different subpopulations of Tfh cells. Nevertheless, these cells are known to promote the differentiation of memory (but not naive) B cells to plasma cells. Dysregulated异常调节activity of conventional and circulating Tfh cells have been found to contribute to autoimmune or immune-deficiency states in several models of human disease. 此外,

尽管一些研究人类循环Tfh细胞,把它定义为所有的CD4 + T细胞仅表达CXCR5 +,而其他的研究表明,CD4 +、CXCR5 + T细胞可以进一步分为PD-1 +,ICOS+,和/或IL-21 +。目前尚不清楚Tfh细胞中不同的亚种：PD1、ICOS或IL-21的表达。然而,这些细胞会促进不同的记忆B细胞分化为血浆细胞。有研究发现，在一些人

类疾病的模型中，传统活性的异常调节和循环Tfh细胞特异表达基因会导致自身免疫或免疫缺陷状态。In addition, circulating Tfh cells have been shown to be biomarkers of effective humoral immunity in vaccination and infectious disease studies. Finally, conventional Tfh(CD4+ CCR5+) cells have been shown to mediate protective immunity against tuberculosis. Thus, while the requirement for Tfh cells in animal models of TB infection is well-defined, the role of circulating Tfh cells in human TB infection and disease has not been explored.此外,循环Tfh细胞已被证实是有效的体液免

疫和传染性疾病研究的疫苗接种生物标记物。因此,传统Tfh(CD4 + CCR5 +)细胞已被证明对肺结核[11]调解

保护性免疫。因此,虽然要求Tfh细胞在动物模型的结核病感染有明确定义，而对人类的结核感染和对疾病的作用尚不清楚。

To study the distribution of Tfh cells in TB infections, we examined Mtb antigen-specific induction Tfh cells subsets (defined as CD4+，CXCR5+，PD-1+，ICOS2 or CD4+，CXCR5+，PD-，ICOS+ or CD4+，CXCR5+，PD-1+，ICOS+) in PTB and LTB individuals in an area highly endemic for tuberculosis. We observed that active PTB was characterized by diminished frequencies of Tfh cells ex vivo and in response to TB antigens and by diminished frequencies Tfh cells producing IL-21, a finding that was reflected in circulating plasma levels of IL-21.

本研究是在结核病感染者中了解Tfh细胞的分布情况,我们检测了Mtb特异性诱导Tfh细胞子集在PTB

和LTB中，一个区域高度流行的肺结核。我们观察到体外培养中PTB Tfh细胞的活性特点是频率降低。针对结核抗原和减少Tfh细胞频率产生IL-21,这一发现是反映在循环等离子IL-21水平。IL-10,CTLA-4 and PD-L1 each appear to play a role in the Tfh homestasis as well. Our data therefore suggest that central defects in Tfh subset differentiation and/or function is a feature of active pulmonary tuberculous disease. IL- 10,CTLA-4和PD-L1似乎扮演一个角色在Tfh homestasis。我们的数据表明,中央缺陷Tfh子集分化和/或功能是活动性肺结核结核性疾病的一个特色。

Study population

We studied a group of 50 individuals; 30 with pulmonary TB(PTB) and 20 individuals with latent TB (LTB). Among the 30 individuals with PTB, 19 of these were also used for antibody blocking studies. Individuals with PTB were diagnosed sputum smear and culture positivity. Individuals with LTB were diagnosed on the basis of being positive in the Quantiferon-TB Gold in Tube (Cellestis) assay but having an absence of pulmonary symptoms concurrent with a normal chest radiograph. All subjects had been bacillus Calmette-Guerin (BCG) vaccinated at birth. All the individuals were HIV negative and blood was collected prior to commencement of anti-TB treatment.我们研究了一群50个人,30与肺结核(PTB)和20个人和潜在的结核病(L TB)。在PTB的30个人,其中19也用于抗体阻断研究。PTB的人被诊断为痰涂片和培养积极性。个人LTB被诊断的基础上,积极在Quantiferon-TB黄金管(Cellestis)测定但缺乏肺并发症状有正常胸部x光照片。所有科目都卡介苗(BCG)出生时接种疫苗。所有的个人都是消极和HIV病毒的血液收集毕业典礼前抗结核治疗。

Antigens抗原

Mycobacterial antigens - PPD (Statens Serum Institute,Copenhagen, Denmark), ESA T-6 and CFP–10 (both from NIAIDTB antigen repository at BEI resources) were used as antigenic stimuli, and anti-CD3 antibody was used as positive control. Final concentrations were 10mg/ml for PPD, ESA T-6 and CFP-10 and 5mg/ml for anti-CD3. For antibody ELISA, PPD and MTB whole cell lysate (WCL) were used as the antigens.分枝杆菌抗原——产后抑郁症(史坦顿血清研究所,哥本哈根,

丹麦),ESAT-6和CFP-10(从NIAIDTB抗原库贝资源)作为抗原刺激,和anti-CD3抗体被用来作为积极的控制。最后10毫克/毫升浓度对产后抑郁症,ESAT-6 anti-CD3 CFP-10和5毫克/毫升。结核分枝杆菌抗体ELISA、产后抑郁症和整个细胞溶解产物(水控制法)作为抗原。

In vitro culture体外培养

Intracellular cytokine staining细胞内因子染色

(ELISA)

Discussion

Infection with Mtb can lead to various outcomes that range from active or chronic pulmonary disease, extra-pulmonary TB and latent TB, that occurs when the initial infection is controlled but not completely eliminated. While a number of host immune mechanisms have been described to play a role in the diverging clinical manifestations of TB infection and disease, the immune mechanisms that contribute directly to disease pathogenesis are still incompletely understood. Tfh cells are a subset of CD4+ T cells that are indispensable for the generation and maintenance of humoral immunity. 结核分枝杆菌感染可以导致不同的结果,从活跃或慢性肺疾病,肺外结核病和潜伏性结核病,发生在最初的感染控制,但不能完全消除。虽然描述了一系列的宿主免疫机制发挥作用的不同临床表现的结核感染和疾病的免疫机制,有助于疾病的发病机制仍不完全清楚。Tfh细胞CD4 + T细胞的一个子集,是不可或缺的生成和维护体液免疫。It has recently been demonstrated that CXCR5+ T cell accumulate within ectopic lymphoid structures associated with TB granulomas in humans,non-human primates and mice. These lymphoid follicles appear to be important for proper localization of T cells in the granulomas, for the optimal activation of macrophages and for protection against TB disease. Thus, while Tfh cells located within the granulomas are clearly important in the immune response to TB, the role of circulating Tfh cells in human TB infection and disease remains unexplored.它最近被证明CXCR5 + T细胞内积累异位淋巴结构在人类与结核肉芽肿,非人类的灵长类动物和老鼠。这些淋巴滤泡似乎重要的适当的本地化的T细胞肉芽肿,最佳活化的巨噬细胞和预防结核病。因此,虽然Tfh细胞位于肉芽肿在结核病免疫反应,显然是重要的角色循环Tfh细胞在人类结核病感染和疾病仍然是未知的。

The distribution of Tfh cells in TB infection and disease was studied by classifying them into 3 subsets. We first attempted to infer the function of these Tfh subsets expressing different combination of surface markers by examining their response to MTB antigens in those with LTB and those with active PTB. Our data clearly reveals that both PD-1 and ICOS either separately or together mark Tfh cells with similar properties in terms of antigenic responsiveness. Tfh细胞结核感染和疾病的分布研究了分类成三个子集。我们第一次试图推断出这些Tfh子集的函数表达不同的表面标记组合通过检查他们对结核分枝杆菌抗原的反应在那些PTB LTB和活跃。我们的数据清楚地表明,PD-1和国际单独或一起马克Tfh细胞具有类似属性的抗原反应。Subsequently,the examination of frequencies of these Tfh subsets revealed asignificant reduction in the frequencies of these subsets in those with PTB. This study demonstrates for the first time, we believe, that there are decreased frequencies of Tfh cells in tuberculosis, data that are in contrast to data from HIV and other viral infections where Tfh frequencies are increased. Thus, PTB appears to be selectively associated with TB - antigen specific deficiency in Tfh cells expressing either ICOS and/or PD-1. One of the major hallmarks of Tfh cells is their ability to produce a variety of cytokines – most notably IL-21. Our examination of the IL-21 expressing Tfh cells in PTB reveals that the diminished frequency of Tfh cells in TB disease translated to diminished function of these cells.随后,这些Tfh子集的检查频率显示乳癌的这些子集的频率在PTB。这项研究首次表明,我们相信,有频率的降低Tfh细胞肺结核、数据与其他数据从艾滋病毒和病毒感染Tfh频率增加。因此,PTB似乎是选择性地与结核病——特定抗原缺乏相关国际和/或PD-1 Tfh细胞表达。Tfh细胞的主要特征之一是他们的能力产生多种细胞因子,尤其是IL-21。我们检查IL-21表达Tfh细胞PTB揭示了降低结核病Tfh细胞转换成频率减少这些细胞的功能。In addition, we also observed significantly diminished systemic levels of IL-21 in PTB and a significant positive correlation between Tfh cell subset frequencies and IL-21 levels in these individuals suggesting that most of the IL-21 in TB infection and disease is probably derived from circulating Tfh cells. Since there are increasing reports of Tfh cells producing other cytokines including IL-4, IFNc and IL-17, we examined the levels of these cytokines and found lower levels of circulating IFNcin

PTB. Thus,we demonstrate that the dysregulated expression of Tfh cell subsets is actually associated with functional impairment of these cells in the circulation of PTB individuals. 此外,我们还观察到显著减少系统性的IL-21 PTB Tfh之间显著正相关细胞频率和IL-21子集水平在这些个人建议的大部分IL-21结核感染和疾病可能是来自循环Tfh细胞。因为越来越多的报道Tfh细胞生产其他细胞因子

包括IL-4,IFNc IL-17,我们检查了这些细胞因子的水平,发现低水平的循环IFNcin PTB。因此,我们证明Tfh

细胞的表达特异表达基因子集实际上是与这些细胞的功能障碍相关的循环PTB个人。It is possible that the diminished frequencies in the blood of PTB individuals is a reflection of increased migration

to the tissues - lungs or mediastinal lymph nodes. However, since circulating Tfh cells have been shown to consistently exhibit additional functions compared to tissue resident Tfh cells, our data hold importance in terms of potential impact on pathogenesis of TB disease.血液中有可能减少频率PTB个人反映增加的移民组织——肺或纵隔淋巴结。然而,由于循环Tfh细胞已被证明始终表现出额外的功能与组织居民Tfh细胞相比,我们的数据保存的重要性对结核病的发病机制的潜在影响。However,we have not examined the frequencies of these cells or that of their hallmark cytokines in healthy control individuals (without latent infection) and therefore need to perform these studies in the future to elucidate the role of these cells and cytokines in TB infection.Another hallmark of Tfh cells is their ability to provide B cell help. Although the role of B cells in TB is not clearly understood, it is known that B cell deficient mice appear more susceptible to TB. Studies of human and non human primate TB granulomas have identified B cell follicle structures that might contribute to the immune response to TB. 然而,我们没有检查的频率,这些细胞或细胞因子在健康的标

志控制个人(没有潜伏性感染),因此需要执行这些研究在未来阐明这些细胞和细胞因子的作用在结核病感染。Tfh细胞的另一个特点是,他们提供B细胞帮助的能力。虽然在结核病B细胞的作用并不清楚,众所周知,B

细胞缺陷小鼠更容易出现结核病。研究人类和非人类灵长类动物的结核肉芽肿都发现B细胞滤泡结构,可能导致结核病的免疫反应。W hile conventional Tfh cells are known to promote all aspects of B cell function, circulating Tfh cells are known only to specifically promote activated and classical memory B cell and plasma cell formation. However, we did not observe any significant compromise in memory B cell formation in PTB nor were there any perturbations in frequencies

of other B cell subsets. Again, we have not estimated the function of these cells directly nor have we estimated the frequency of these cells in healthy control individuals (without latent infection).

虽然传统Tfh细胞促进B细胞功能的各个方面,循环Tfh细胞只有专门促进激活和古典知道记忆B细胞和浆细胞的形成。然而,我们没有观察到任何重大妥协在PTB记忆B细胞的形成也不再有任何扰动频率的B细胞的子集。再一次,我们没有直接估计这些细胞的功能我们估计也没有控制这些细胞在健康个体的频率(没有潜伏性感染)。

Although it is known that numerous cytokines can promote Tfh formation, much less is known about the factors that restrain this process. It has been reported that Tfh cell formation can be suppressed by several cytokines, including IL-10 and TGFb. Indeed, we also detected increased levels of IL-10 in circulation in PTB individuals. Coupled with data on the blockade of IL-10 in PTB individuals, it appears that IL-10 does indeed play an important role in the modulation of Tfh cells in active PTB. On the other hand, TGF (beita)appears to play a negligible role in the regulation of Tfh cells in active TB. Although PD-1 is highly expressed in Tfh cells, little is known about the role of PD-1 in Tfh cell development and function.虽然众所周知,许多细胞因子能

促进Tfh形成,不太了解的因素抑制这一过程。据报道,Tfh可以抑制细胞的形成一些细胞因子,包括il - 10和TGFb。实际上,我们还发现增加流通中的il - 10在PTB个人的水平。加上数据的封锁在PTB il - 10个人,看来il - 10确实发挥重要作用的调制Tfh PTB细胞活跃。另一方面,TGF(beita)扮演一个微不足道的角色出现

在Tfh细胞活动性结核病的监管。虽然PD-1 Tfh细胞高表达,很少被人所知的角色在Tfh PD-1细胞发育和

功能。Studies in mice deficient in PD-1 or its ligands report increased numbers of Tfh cells, suggesting that PD-1/PD-L1 interactions downregulate Tfh generation and/or differentiation [20]. While CTLA-4 is a potent inhibitor of effector T cell differentiation and function [21], its role in regulating Tfh cell expansion is not known. Interestingly, our study reveals an important role for both PD-1 and CTLA-4 signaling in the down modulation of Tfh cell expansion in pulmonary TB since blockade of either of these pathways significantly restored the TB – antigen induced expansion of Tfh cell subsets in PTB individuals. 研究小鼠缺乏PD-1或其配体报告Tfh细胞数量的增加,表明PD-1 / PD-L1交互Tfh代表达下调和/或分化[20]。虽然CTLA-4是一个强有力的抑制剂效应T细胞分化和功能[21],它的作用在调节Tfh细胞扩张是未知的。有趣的是,我们的研究揭示了一个重要的角色对于PD-1和CTLA-4下调制信号的Tfh细胞扩张以来,肺结核的封锁这些通路显著恢复结核病——抗原诱导PTB 个人Tfh细胞子集的扩张。These data provide novel insights into the role of PD-1 and CTLA-4 on the regulation of Tfh cells in a human infectio and suggest that imporant new roles for these molecules apart from their effect on T effector cells.这些数据提供新颖的见解PD-1的角色和CTLA-4 Tfh细胞调节的人类感染个案和认为重要的新角色这些分子除了影响的效应细胞。

In summary, our data on the Tfh cell distribution and function in pulmonary tuberculosis suggest that compromised Tfh cell numbers and function are a prominent feature of active disease.Although our study was not designed to decipher cause and effect mechanisms of Tfh association with active TB, it nevertheless implicates an important role for this poorly explored subset of CD4+ T cells in active TB. Our study also provides the first comprehensive analysis of the distribution of B cell subsets in pulmonary TB and reveals that compromised B cell subset distribution is not a feature of active TB disease. Our data also suggest that adjunct

immuno-modulation in the form of coinhibitory receptor blockade (or immune checkpoint blockade using CTLA-4 and PD-1 antagonists) could potentially also enhance the protective immune responses of susceptible individuals.总之,我们的数据在肺结核Tfh细胞分布和功能表明,妥协Tfh细胞数量和功能是活动性疾病的显著特征。虽然我们的研究不是为了解释因果机制Tfh与活动性结核病,然而牵连到一个重要的角色对于这糟糕的探索子集CD4 + T细胞在活动性结核病。我们的研究也提供了第一个综合分析B细胞分布的子集在肺结核和显示,妥协B细胞分布不是活动性结核患者的特征子集。我们的数据也表明,兼职的形式immuno-modulation coinhibitory受体封锁(或免疫检查点封锁使用CTLA-4和PD-1拮抗剂)也有可能增强易感个体的保护性免疫反应。