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.     

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.     

CD4+CD25+调节性T细胞在约氏疟原虫感染早期作用机制的实验研究

目的探讨CD4^＋CD25^＋调节性T细胞在约氏疟原虫感染早期的免疫调节机制。方法用抗CTLA-4 mAb和抗CD25 mAb分别与约氏疟原虫感染早期的小鼠脾细胞共同培养后,以ELISA法检测其培养上清的IL-10、TGF-β1及IFN-γ的含量。结果与抗CTLA-4 mAb共同培养后,脾细胞上清中IL-10的水平明显降低,但TGF-β1和IFN-γ水平未出现有意义的变化;与抗-CD25 mAb共同培养后,IL-10、TGF-β1和IFN-γ水平均未出现有意义的变化,但IL-10水平有一定的降低趋势。结论约氏疟原虫感染早期,IL-10可能是介导CD4^＋CD25^＋调节性T细胞参与免疫调节的关键性细胞因子,CD4^＋CD25^＋调节性T细胞可能通过CTLA-4发挥免疫抑制作用。     

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.     

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.     

Age-dependent changes in T follicular helper cells shape the humoral immune response to vaccination

Vaccination is an excellent strategy to limit the morbidity and mortality associated with infectious disease. Vaccination creates protective, long-lived antibody-mediated immunity by inducing the germinal centre response, an intricate immune reaction that produces memory B cells and long-lived antibody-secreting plasma cells that provide protection against (re)infection. The magnitude and quality of the germinal centre response declines with age, contributing to poor vaccine-induced immunity in older individuals. T follicular helper cells are essential for the formation and function of the germinal centre response. This review will discuss how age-dependent changes in T follicular helper cells influence the germinal centre response, and the evidence that age-dependent changes need not be a barrier to successful vaccination in the later years of life.     

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.     

Using two phases of the CD4 T cell response to blood-stage murine malaria to understand regulation of systemic immunity and placental pathology in Plasmodium falciparum infection

Plasmodium falciparum infection and malaria remain a risk for millions of children and pregnant women. Here, we seek to integrate knowledge of mouse and human T helper cell (Th) responses to blood-stage Plasmodium infection to understand their contribution to protection and pathology. Although there is no complete Th subset differentiation, the adaptive response occurs in two phases in non-lethal rodent Plasmodium infection, coordinated by Th cells. In short, cellular immune responses limit the peak of parasitemia during the first phase; in the second phase, humoral immunity from T cell–dependent germinal centers is critical for complete clearance of rapidly changing parasite. A strong IFN-γ response kills parasite, but an excess of TNF compared with regulatory cytokines (IL-10, TGF-β) can cause immunopathology. This common pathway for pathology is associated with anemia, cerebral malaria, and placental malaria. These two phases can be used to both understand how the host responds to rapidly growing parasite and how it attempts to control immunopathology and variation. This dual nature of T cell immunity to Plasmodium is discussed, with particular reference to the protective nature of the continuous generation of effector T cells, and the unique contribution of effector memory T cells.     

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.     

CTLA-4 x Ig converts naive CD4+CD25- T cells into CD4+CD25+ regulatory T cells

CTLA-4 x Ig was originally designed as an immunosuppressive agent capable of interfering with the co-stimulation of T cells. In the present study, we demonstrate that CTLA-4 x Ig, in combination with TCR ligation, has the additional capacity to convert naive CD4+CD25- T cells into Foxp3+ regulatory T (T(reg)) cells, as well as to expand their numbers. The CD4+CD25+Foxp3+ T(reg) generated by CTLA-4 x Ig treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4 x Ig increases the percentage of CD4+CD25(hi)Foxp3+ cells within mixed lymphocyte reaction-induced murine lymph nodes. Significantly, the in vitro conversion of naive CD4+CD25- T cells into T(reg) cells is antigen-presenting cell (APC) dependent. This finding, together with the further observation that this conversion can also be driven in vitro by an antibody that engages B7-2 ligand, suggests that CTLA-4 x Ig-driven T(reg) induction may be predicated upon active CTLA-4 x Ig to B7-2 signaling within APC, which elicits from them T(reg)-inducing potential. These findings extend CTLA-4 x Ig's functional repertoire, and at the same time, reinforce the concept that T cell anergy and active suppression are not entirely distinct processes and may be linked by some common molecular triggers.     

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

Germinal centers (GC) have been known as key anatomic structures in humoral immunity, where isotype switching and affinity maturation occur. As a consequence, elucidation of GC regulation has potential implications for the understanding of autoantibody‐mediated diseases. It is now accepted that different regulatory mechanisms coexist, including the action of a specialized population of Foxp3⁺ regulatory T cells with unique access to the B‐cell follicle: the T follicular regulatory (Tfr) cells. Tfr cells develop through a multistep process requiring migration through different compartments of lymphoid tissues. This review discusses the ontogeny and physiology of Tfr cells, their distribution within distinct anatomic compartments, and their function. A greater understanding of Tfr biology and GC regulation is likely to lead to better stratification of patients with autoantibody‐mediated diseases, and to the identification of novel therapeutic targets.     

Induction of peripheral blood T follicular helper cells expressing ICOS correlates with antibody response to hepatitis B vaccination

T follicular helper (TFH) cells, a critical subset of CD4⁺ T cells, provide help to B cells during the procession of the humoral immune response in the germinal center (GC) and extrafollicular sites. CXCR5⁺CD4⁺ T cells in human circulating blood, referred to herein as peripheral TFH (pTFH) cells, share phenotypes and functional properties with TFH cells in GC. Hepatitis B vaccine protects about 60% of the chronic hepatitis C patients from hepatitis B. The immunological bases that lead to the induction of protective antibody response is not well understood. In the present study, the pTFH cells subsets were determined in 18 healthy controls (anti-HBs ≥ 100 mIU/mL; HC), 21 nonresponders (anti-HBs < 10 mIU/mL; NR), and 23 weak responders (10 mIU/mL ≤ anti-HBs < 100 mIU/mL; WR) of chronic hepatitis patients upon routine hepatitis B vaccination. Though the frequency of the pTFH cell was equivalent in HC, WR, and NR, ICOS⁺pTFH cells in HC underwent expansion with increased IL-21 secretion and production of serum anti-HBs response at 4 weeks after a full course of hepatitis B vaccination. These changes were not shown in both NR and WR. Analysis of ICOS⁺pTFH cells represents a novel cellular determinant of the hepatitis B vaccine–induced humoral immune response, which may have relevance for design of hepatitis B vaccine.     

The regulation and role of T follicular helper cells in immunity

It is well established that the generation of a high-affinity long-lived antibody response requires the presence of T cells, specifically CD4+ T cells. These CD4+ T cells support the generation of a germinal centre (GC) response where somatic hypermutation and affinity maturation take place leading to the generation of memory B cells and plasma cells, which provide long-lasting protection. Greater insight into the nature of the CD4+ T cells involved in this process was provided by two studies in 2000 that described CD4+ T cells residing in the B cell follicle that expressed CXCR5. As a result these cells were named follicular B helper T cells, now more commonly known as T follicular helper (Tfh) cells. Since then there has been enormous growth in our understanding of these cells, now considered a distinct T helper (Th) cell lineage that can arise from naive CD4+ T cells following activation. This review summarizes some of the most recent work that has characterized Tfh cells and the pathways that lead to their generation.     

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.     

A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC

Nectins and Nectin‐like molecules (Necl) play a critical role in cell polarity within epithelia and in the nervous and reproductive systems. Recently, immune receptors specific for Nectins/Necl have been described. Since the expression and distribution of Nectins/Necl is often subverted during tumorigenesis, it has been suggested that the immune system may use these receptors to recognize and eliminate tumors. Here we describe a novel immunoreceptor, Washington University Cell Adhesion Molecule, which is expressed on human follicular B helper T cells (TFH) and binds a Nectin/Necl family member, the poliovirus receptor (PVR), under both static and flow conditions. Furthermore, we demonstrate that PVR is abundantly expressed by follicular DC (FDC) within the germinal center. These results reveal a novel molecular interaction that mediates adhesion of TFH to FDC and provide the first evidence that immune receptors for Nectins/Necl may be involved the generation of T cell‐dependent antibody responses.     

卵巢癌细胞培养上清诱导CD4+CD25-T细胞分化为CD4+CD25+调节性T细胞

目的研究卵巢癌细胞培养上清液是否能诱导外周血CD4^＋CD25^- T细胞转变为CD4^＋CD25^＋调节性T细胞。方法将外周血CD4^＋CD25^- T细胞分离后，对照组用CD3和CD28单抗活化，实验组在对照基础上加用卵巢癌细胞株SKOV3培养上清，72h后分离各组的CD25^＋和CD25^-T细胞，溴化脱氧尿嘧啶掺入标记法测定增殖能力及对静息的自体同源CD4^＋CD25^- T细胞的增殖抑制能力，流式细胞仪测定细胞糖皮质激素诱发型TNF受体（glucocorticoid-induced TNFR,GITR）与CTLA-4分子的表达，RT-PCR检测细胞卿mRNA的表达。结果与对照组相反，实验组的CD4^＋CD25^＋T细胞具有免疫抑制功能，自身增殖能力下降，GITR和CTLA-4分子的表达和CD4^＋CD25^＋调节性T细胞相似，并被诱导表达转录因子Foxp3 mRNA。结论卵巢癌细胞分泌的可溶性物质能诱导外周血CD4^＋CD25^-T细胞转化为CD4^＋CD25^＋调节性T细胞。     

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.