Differential regulation of transcription factor T-bet induction during NK cell development and T helper-1 cell differentiation

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T follicular helper cell heterogeneity: Time,space, and function

T follicular helper (Tfh) cells play a crucial role in orchestrating the humoral arm of adaptive immune responses. Mature Tfh cells localize to follicles in secondary lymphoid organs (SLOs) where they provide help to B cells in germinal centers (GCs) to facilitate immunoglobulin affinity maturation, class‐switch recombination, and generation of long‐lived plasma cells and memory B cells. Beyond the canonical GC Tfh cells, it has been increasingly appreciated that the Tfh phenotype is highly diverse and dynamic. As naive CD4⁺ T cells progressively differentiate into Tfh cells, they migrate through a variety of microanatomical locations to obtain signals from other cell types, which in turn alters their phenotypic and functional profiles. We herein review the heterogeneity of Tfh cells marked by the dynamic phenotypic changes accompanying their developmental program. Focusing on the various locations where Tfh and Tfh‐like cells are found, we highlight their diverse states of differentiation. Recognition of Tfh cell heterogeneity has important implications for understanding the nature of T helper cell identity specification, especially the plasticity of the Tfh cells and their ontogeny as related to conventional T helper subsets.     

Human T helper type 1 dichotomy: origin,phenotype and biological activities

The great variety of pathogens present in the environment has obliged the immune system to evolve different mechanisms for tailored and maximally protective responses. Initially, two major types of CD4⁺ T helper (Th) effector cells were identified, and named as type 1 (Th1) and type 2 (Th2) cells because of the different cytokines they produce. More recently, a third type of CD4⁺ Th effectors has been identified and named as Th17 cells. Th17 cells, however, have been found to exhibit high plasticity because they rapidly shift into the Th1 phenotype in the inflammatory sites. Therefore, in these sites there is usually a dichotomous mixture of classic and non-classic (Th17-derived) Th1 cells. In humans, non-classic Th1 cells express CD161, as well as the retinoic acid orphan receptor C, interleukin-17 receptor E (IL-17RE), IL-1RI, CCR6, and IL-4-induced gene 1 and Tob-1, which are all virtually absent from classic Th1 cells. The possibility to distinguish between these two cell subsets may allow the opportunity to better establish their respective pathogenic role in different chronic inflammatory disorders. In this review, we discuss the different origin, the distinctive phenotypic features and the major biological activities of classic and non-classic Th1 cells.     

B cell helper T cells and type 1 diabetes

Type 1 diabetes is an autoimmune disease typically starting in childhood that culminates in the destruction of insulin-producing beta cells in the pancreas. Although type 1 diabetes is considered to be a primarily T cell–mediated disease, B cells clearly participate in the autoimmune process, as autoantibodies recognizing pancreatic islet antigen commonly appear in circulation before the onset of the disease. T cells providing helper functions to B cells have recently been shown to be involved in the pathogenesis of a wide range of antibody-associated immune disorders. These T cells include CXCR5-positive follicular T helper (Tfh) cells, and a recently described closely related CXCR5-negative subset coined peripheral T helper (Tph) cells. Here, we review the current state of knowledge on different B cell helper T cell subsets, focusing on their potential involvement in the development of type 1 diabetes.     

辅助T细胞分化的表观遗传学调控

在抗原的刺激下,CD4^＋辅助性T细胞（Th细胞）可分化为不同的细胞亚群以对抗不同的外界环境。Th细胞的分化主要受细胞因子、细胞特异性转录因子等调控。近年来研究发现,DNA甲基化、组蛋白修饰以及染色质重塑等表观遗传学修饰能调控相关基因的表达,使Th细胞分化成稳定的亚群,发挥相应的功能。同时,这些表观遗传学修饰机制在赋予Th细胞亚群可遗传性、可塑性等方面也发挥着重要的作用。     

Distinct T helper cell dependence of memory B‐cell proliferation versus plasma cell differentiation

Several memory B‐cell subclasses with distinct functions have been described, of which the most effective is the class‐switched (CS) memory B‐cell population. We have previously shown, using virus‐like particles (VLPs), that the proliferative potential of these CS memory B cells is limited and they fail to re‐enter germinal centres (GCs). However, VLP‐specific memory B cells quickly differentiated into secondary plasma cells (PCs) with the virtue of elevated antibody production compared with primary PCs. Whereas the induction of VLP⁺ memory B cells was strongly dependent on T helper cells, we were wondering whether re‐stimulation of VLP⁺ memory B cells and their differentiation into secondary PCs would also require T helper cells. Global absence of T helper cells led to strongly impaired memory B cell proliferation and PC differentiation. In contrast, lack of interleukin‐21 receptor‐dependent follicular T helper cells or CD40 ligand signalling strongly affected proliferation of memory B cells, but differentiation into mature secondary PCs exhibiting increased antibody production was essentially normal. This contrasts with primary B‐cell responses, where a strong dependence on CD40 ligand but limited importance of interleukin‐21 receptor was seen. Hence, T helper cell dependence differs between primary and secondary B‐cell responses as well as between memory B‐cell proliferation and PC differentiation.     

The hippo kinase MST1 negatively regulates the differentiation of follicular helper T cells

Follicular helper T (T_FH) cells are essential for inducing germinal centre (GC) reactions to mediate humoral adaptive immunity and antiviral effects, but the mechanisms of T_FH cell differentiation remain unclear. Here, we found that the hippo kinase MST1 is critical for T_FH cell differentiation, GC formation, and antibody production under steady-state conditions and viral infection. MST1 deficiency intrinsically enhanced T_FH cell differentiation and GC reactions in vivo and in vitro. Mechanistically, mTOR and HIF1α signalling is involved in glucose metabolism and increased glycolysis and decreased OXPHOS, which are critically required for MST1 deficiency-directed T_FH cell differentiation. Moreover, upregulated Foxo3 expression is critically responsible for T_FH cell differentiation induced by Mst1^−/−. Thus, our findings identify a previously unrecognized relationship between hippo kinase MST1 signalling and mTOR-HIF1α-metabolic reprogramming coupled with Foxo3 signalling in reprogramming T_FH cell differentiation.     

Biological and clinical significance of T helper 17 cell plasticity

Mature T helper (Th) effector cells originate following antigen recognition by naive T precursors. The maturation process is accompanied by the acquisition of specific effector functions that distinguish at least three different T helper subsets: Th1, Th2 and Th17. In general, maturation of somatic cells is accompanied by terminal differentiation. However, accumulating evidence shows that effector T cells retain a certain degree of plasticity. This is especially true for Th17 cells, which have been shown to converge towards other phenotypes in response to specific microenvironmental pressure. In this review we will discuss the experimental evidence that supports the hypothesis of Th17 plasticity, with particular emphasis on the generation of Th17-derived ‘non-classic’ Th1 cells, and the molecular networks that control it. Moreover, we will consider why Th17 plasticity is important for host protection, but also why it can have pathogenic functions during chronic inflammation. Regarding the last point, we will discuss a possible role for biological drugs in the control of Th17 plasticity and disease course.     

Default polyfunctional T helper 1 response to ample signal 1 alone

CD4⁺ T cells integrate well-defined signals from the T-cell receptor (TCR) (signal 1) and a host of costimulatory molecules (signal 2) to initiate clonal expansion and differentiation into diverse functional T helper (Th) subsets. However, our ability to guide the expansion of context-appropriate Th subsets by deploying these signals in vaccination remains limited. Using cell-based vaccines, we selectively amplified signal 1 by exclusive presentation of an optimized peptide:MHC II (pMHC II) complex in the absence of classic costimulation. Contrary to expectations, amplified signal 1 alone was strongly immunogenic and selectively expanded high-affinity TCR clonotypes, despite delivering intense TCR signals. In contrast to natural infection or standard vaccines, amplified signal 1, presented by a variety of professional and nonprofessional antigen-presenting cells (APCs), induced exclusively polyfunctional Th1 effector and memory cells, which protected against retroviral infection and tumor challenge, and expanded tumor-reactive CD4⁺ T cells otherwise rendered unresponsive in tumor-bearing hosts. Together, our findings uncover a default Th1 response to ample signal 1 and offer a means to selectively prime such protective responses by vaccination.     

类风湿性关节炎患者外周血TH1/TH2细胞的研究

目的探讨CD4+TH1/TH2细胞在类风湿性关节炎(RA)发生发展过程中的作用.方法采用酶联免疫斑点法(ELISPOT)对15例RA患者和30例健康人外周血中T淋巴细胞亚群及CD4+TH1/TH2功能亚型进行检测.结果RA患者外周血中TH1细胞的百分率较正常对照组升高(P＜0.05).结论 TH1细胞介导的细胞免疫可能与RA的发生发展有关.     

Aire deficient dendritic cells promote the T follicular helper cells differentiation

Autoimmune regulator (Aire), primarily expressed in medullary thymic epithelial cells (mTECs), maintains central immune tolerance through the clearance of self-reactive T cells. Aire can also be expressed in dendritic cells (DCs), and DCs can mediate T follicular helper (T_FH) cell differentiation and self-reactive B cell activation through inducible costimulator molecule ligand (ICOSL) and interleukin 6 (IL-6), which can cause autoimmune diseases. To confirm whether Aire in DCs affects T_FH cell differentiation and to determine the role of Aire in the maintenance of peripheral immune tolerance, this study observed the effects of Aire deficiency on T_FH cells using Aire knockout mice. The results showed that Aire deficiency caused increased number of T_FH cells, both in vivo and in vitro. Further studies showed that Aire deficiency promoted T_FH differentiation through the upregulation of ICOSL and IL-6 in DCs. Thus Aire could suppress the expression of ICOSL and IL-6 to inhibit T_FH cell differentiation.     

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.     

类风湿关节炎患者外周血Tfh及Th9的变化及临床意义

目的 观察类风湿关节炎(RA)患者外周血中滤泡辅助性T细胞(Tfh)及T辅助细胞9(Th9)的变化,并与病情活动性及脏器受累等临床资料进行相关性分析,探讨Tfh及Th9在RA发病过程中可能的免疫学发病机制.方法 选择36例RA患者和22例健康对照.根据病情活动度不同将病例组分为病情高度活动组(22例)、病情中度活动组(14例),流式细胞仪检测RA和正常对照组外周血单个核细胞( PBMCs)中CD4-FITC、CXCR5-PE、ICOS-APC标记的CD4+ CXCR5+ ICOS+(Tfh)及CD8-FITC、CD3-APC、IL9-PE标记的CD3+CD8-IL-9+( Th9)比例.分析Tfh及Th9与RA患者的血沉(ESR)、C反应蛋白(CRP)、类风湿因子(RF)、关节压痛数、肿胀数及骨质破坏等指标的相关性;分析Tfh与Th9的关系.结果 RA患者的Tfh表达率明显高于对照组(Z=-6.082,P=0.000),RA患者Th9的表达率亦高于对照组(0.989±0.498 vs 0.213 ±0.084,t=13.063,P=0.000);RA重度活动组Tfh表达率亦高于中度活动患者的表达率(3.880±1.255 vs 2.678±1.022,t=2.990,P=0.005),且两组Tfh的表达率均高于对照组(P均＜0.01);RA重度活动患者Th9表达率高于中度患者(1.181±0.523 vs 0.686±0.254,t=4.043,P=0.000),且两组Th9的表达率亦均高于对照组(P均＜0.01); Tfh 细胞数与RA患者DAS28(r=0.571,P=0.000)、ESR(r=0.375,P=0.029)、CRP(r=0.357,P=0.032)、关节压痛数(r=0.598,P=0.000)、RF(r=0.421,P=0.023)及抗CCP滴度(r=0.421,P=0.023)正相关;与病程、晨僵、关节肿胀数、骨质破坏、心电图异常无相关性.Th9表达的百分率与RA患者的DAS28( r=0.461,P=0.005)、ESR(r=0.347,P=0.042)、CRP(r=0.384,P=0210)、关节压痛数(r=0.341,P=0.042)、关节肿胀数(r=0.347,P=0.038)及RF(r=0.379,P=0.025)正相关,与病程、晨僵时间、抗CCP滴度、心电图异常及骨质破坏无相关性;Tfh与Th9在外周血中的表达率呈正相关(r=0.727,P=0.000).结论 RA患者外周血Tfh及Th9的比例显著升高,且与疾病活动度及相关炎症指标明显相关,提示Tfn及Th9可能参与RA的发病及病情发展.     

滤泡辅助性T细胞分化及其在HIV感染中的变化

T细胞辅助B细胞是适应性免疫和免疫记忆生成的基础.滤泡辅助性T细胞(Tfh)是辅助B细胞的主要T细胞亚群,其主要转录因子为Bcl6.Tfh细胞的明显特征为表达CXCR5、程序性死亡因子-1(PD-1)、IL-21和ICOS,同时Blimp-1表达下调.在HIV-1慢性感染过程中Tfh细胞累积增多,从而导致B细胞调节异常,发生功能性改变,这可能是HIV-1逃避体液免疫应答的根源.     

CD4+ T helper 2 cells--microbial triggers, differentiation requirements and effector functions

Over the past 10 years we have made great strides in our understanding of T helper cell differentiation, expansion and effector functions. Within the context of T helper type 2 (Th2) cell development, novel innate‐like cells with the capacity to secrete large amounts of interleukin‐5 (IL‐5), IL‐13 and IL‐9 as well as IL‐4‐producing and antigen‐processing basophils have (re)‐emerged onto the type 2 scene. To what extent these new players influence αβ⁺ CD4⁺ Th2 cell differentiation is discussed throughout this appraisal of the current literature. We highlight the unique features of Th2 cell development, highlighting the three necessary signals, T‐cell receptor ligation, co‐stimulation and cytokine receptor ligation. Finally, putting these into context, microbial and allergenic properties that trigger Th2 cell differentiation and how these influence Th2 effector function are discussed and questioned.