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Follicular helper T cells (Tfh) are a Th cell subset that directly assists B cells in functioning, and their development is regulated by various factors. Among them, the initial regulation leads to phenotypic heterogeneity, while the regulation of their migration process results in spatial heterogeneity. The phenotypic heterogeneity is manifested by the presence of Tfh subsets with characteristics helper T cells (Th) of other lineages, namely Tfh1, Tfh2, and Tfh17, with different transcriptional programs and secrete distinct cytokines, potentially possessing different functions. The spatial heterogeneity is mainly manifested by the positional relationship between Tfh and germinal centers (GC), which are mainly divided into GC-Tfh, follicular mantle Tfh, and circulating Tfh, possibly reflecting the process of Tfh occurrence. This review summarizes the spatial and phenotypic heterogeneity of Tfh cells, and suggests a Tfh cell type framework with nodes of previous studied cell types and the edges of switching between specific celltypes, which is affected by the summation of imprinted plasticity part and de novo plasticity part in Tfh development, connecting the hypothesis Crotty et al. proposed in 2018. Discrete cell type is still eligible in qualifying the diseases state and quantifying the activity and severity of diseases, but it could also be beneficial to look Tfh from the view of cell states and expression programs, which, in the future studies, might better model the through process of Tfh development and unifying the contradiction caused by separate Tfh cell type view.

Background An estimated 5–10 % of healthy vaccinees lack adequate antibody response following receipt of a standard three-dose hepatitis B vaccination regimen. The cellular mechanisms responsible for poor immunological responses to hepatitis B vaccine have not been fully elucidated to date. Methods There were 61 low responders and 56 hyper responders involved in our study. Peripheral blood samples were mainly collected at D7, D14 and D28 after revaccinated with a further dose of 20 µg of recombinant hepatitis B vaccine. Results We found low responders to the hepatitis B vaccine presented lower frequencies of circulating follicular helper T (cTfh) cells, plasmablasts and a profound skewing away from cTfh2 and cTfh17 cells both toward cTfh1 cells. Importantly, the skewing of Tfh cell subsets correlated with IL-21 and protective antibody titers. Based on the key role of microRNAs involved in Tfh cell differentiation, we revealed miR-19b-1 and miR-92a-1 correlated with the cTfh cell subsets distribution and antibody production. Conclusions Our findings highlighted a decrease in cTfh cells and specific subset skewing contribute to reduced antibody responses in low responders.

MicroRNAs (miRNAs) are small endogenous noncoding RNAs that regulate genome expression posttranscriptionally and are involved in autoimmune diseases. Previous studies have indicated that follicular helper T (Tfh) cells play a critical role in the pathogenesis of Graves’ disease (GD). However, the molecular mechanisms that contribute to circulating Tfh memory cell response in GD patients remain incompletely understood. This study aimed to investigate the role of miRNAs on circulating Tfh memory cells in GD patients. Herein, our data showed that the proportion of circulating Tfh memory cells, the transcript levels of IL-21, and the plasma concentrations of IL-21 were increased in the peripheral blood from GD patients. We also found that inducible co-stimulator (ICOS) expression, an important molecule expressed on Tfh cells, were significantly augmented in the peripheral blood mononuclear cells (PBMCs) from GD patients and positively correlated with the percentage of circulating Tfh memory cells and the transcript levels of IL-21 in GD. Intriguingly, miRNA sequencing screened miR-29a-3p expression was downregulated and inversely correlated with ICOS expression and the frequency of circulating Tfh memory cells in patients with GD. Luciferase assay demonstrated that ICOS was the direct target gene of miR-29a-3p, and miR-29a-3p could inhibit ICOS at both transcriptional and translational levels. Overexpression of miR-29a-3p reduced the proportion of circulating Tfh memory cells. Moreover, miR-29a-3p expression negatively correlated with serum concentrations of TSH receptor antibody (TRAb) in GD patients. Collectively, our results demonstrate that miR-29a-3p emerges as a post-transcriptional brake to limit circulating Tfh memory cell response in GD patients and may be involved in the pathogenesis of GD.

FoxP3 follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue. To understand the biology of Tfr cells in kidney transplant patients treated with tacrolimus and mycophenolate mofetil (MMF) combination immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood by flow cytometry in = 211 kidney transplant recipients. At the time of measurement patients were 5-7 years after transplantation. Of this cohort of patients, 23.2% (49/211) had been previously treated for rejection. Median time after anti-rejection therapy was 4.9 years (range 0.4-7 years). Age and gender matched healthy individuals served as controls. While the absolute numbers of cTfh cells were comparable between kidney transplant recipients and healthy controls, the numbers of cTfr cells were 46% lower in immunosuppressed recipients ( < 0.001). More importantly, in transplanted patients, the ratio of cTfr to cTfh was decreased (median; 0.10 vs. 0.06), indicating a disruption of the balance between cTfr and cTfh cells. This shifted balance was observed for both non-rejectors and rejectors. Previous pulse methylprednisolone or combined pulse methylprednisolone + intravenous immunoglobulin anti-rejection therapy led to a non-significant 30.6% (median) and 51.2% (median) drop in cTfr cells, respectively when compared to cTfr cell numbers in transplant patients who did not receive anti-rejection therapy. A history of alemtuzumab therapy did lead to a significant decrease in cTfr cells of 85.8% (median) compared with patients not treated with anti-rejection therapy ( < 0.0001). No association with tacrolimus or MMF pre-dose concentrations was found. This cross-sectional study reveals that anti-rejection therapy with alemtuzumab significantly lowers the number of cTfr cells in kidney transplant recipients. The observed profound effects by these agents might dysregulate cTfr functions.

Inflammation is known to be involved in the progression of diabetic retinopathy. Follicular helper T cells (Tfh) play critical roles in the differentiation of long-live plasma cells and production of antibodies, whereas circulating CD4+CXCR5+ T cells may act as a counterpart to measure Tfh cell disorders. In this study, we investigated whether Tfh could be involved in the development of diabetic retinopathy (DR) by assessing circulating Tfh cells in peripheral blood. Data showed that serum levels of total IgG and IgA were both significantly increased in type 2 diabetes mellitus (T2DM) patients with proliferative diabetic retinopathy (PDR) than with non-PDR. Also, B cell activation and differentiation were both enhanced in T2DM patients with PDR. Little changes were detected in levels of Th1, Th2, and Th17 cells. As indicated by elevated serum levels and supernatant from cultured PBMC of IL-21, we found increased circulating Tfh cells in PDR patients with dysregulated subsets. This study suggests the involvement of circulating Tfh cells in DR and, in particular, the pathogenesis of PDR.

Allergic rhinitis (AR) is characterized by type I hypersensitivity that is mediated by IgE-induced humoral responses. Follicular helper T cells (Tfh) comprise the key helper T cell (Th) subset that promotes antibody production. Signaling lymphocytic activation molecules (SLAMs) participate in regulation of the differentiation and function of Tfh cells, but whether this regulation is involved in the pathogenesis of AR is unknown. CD4+CXCR5+ Tfh-like cells from peripheral blood were detected by flow cytometry. The IL-21 and IgE levels in serum were measured by an ELISA. Blood CD4+CXCR5+ Tfh-like cells were sorted and cultured with anti-SLAM mAb in vitro. The frequencies of circulating CD4+CXCR5+ Tfh-like cells appeared virtually unchanged in AR patients, but the expression of SLAMs and SLAM-associated protein (SAP) on circulating Tfh-like cells was significantly decreased. Meanwhile, the level of serum IL-21 was increased in AR patients, and a negative correlation was found between the IL-21 level and SLAM or SAP expression on CD4+CXCR5+ T cells. Treatment with anti-SLAM mAb resulted in reduced IL-21 production by Tfh-like cells in vitro. Additionally, SLAM expression on B cells was significantly decreased, although the percentages of B cells were increased in AR patients. SLAMs negatively regulate IL-21 production in CD4+CXCR5+ Tfh-like cells, which contributes to the pathogenesis of AR.

Multiple perturbations of the immune response affecting a range of cells have been reported in -infected individuals and associated to clinical manifestations of chronic Chagas disease. There is a paucity of knowledge about the role of T follicular helper (Tfh) cells in this infection. Here, we sought to characterize circulating Tfh (cTfh) cells in chronic Chagas disease patients and to identify potential associations with disease severity in humans. cTfh cells were characterized by flow cytometry in freshly isolated PBMCs from 7 -infected asymptomatic patients (ASYMP), 5 patients with chronic chagasic dilated cardiomyopathy (CCC) and 8 healthy controls, using antibodies against chemokine receptors CXCR5, CXCR3, CCR6, and CCR7. Our results showed significant expansion of CD4+CD45RO+CXCR5+CCR6+ cells in ASYMP and CCC patients, along with a contraction of CD4+CD45RO+CXCR5+CXCR3-CCR6- (cTfh2) cells. ASYMP patients further exhibited decreased CD4+CD45RO+CXCR5+CXCR3+CCR6- (cTfh1) cells and expanded CD4+CD45RO+CXCR5+CXCR3-CCR6+ (cTfh17) cells while CCC patients exhibited significantly increased frequencies of CD4+CD45RO+CXCR5+CCR7+ cells. Linear regression analysis revealed a positive trend of CD4+CD45RO+CXCR5+CXCR3+CCR6+ (cTfh1/17) cells and negative trends of cTfh1 and cTfh2 cells as disease was more severe. There was no correlation between the frequencies of cTfh cells and circulating CD19+IgD-IgG+ cells or serum levels of -specific IgG. These results demonstrate that the cTfh compartment of humans chronically infected with comprises expanded CCR6-expressing cells and reduced cTfh2 cells. The association of discrete phenotypic changes in cTfh subsets with different clinical forms suggests the potential contribution of T follicular helper cells to Chagas heart disease progression.

Background The seroconversion rate after hepatitis B virus (HBV) vaccination in people living with human immunodeficiency virus (HIV) is reportedly lower than that in non-HIV controls. Follicular helper T (Tfh) cells play a central role in humoral immunity, and IL-21 secreted by Tfh cells is essential for B cells to differentiate into plasma cells. This study investigated the frequency and function of circulating Tfh (cTfh) cells isolated from people living with HIV (PWH) who are negative for hepatitis B virus (HBV) surface antigen (HBsAb−) in a small cohort of PWH who received HBV vaccination. Case presentation The frequency of cTfh cells in HBsAb− PWH (HBsAb levels less than 10 mIU/mL) was the same as that in non-HIV controls and HBsAb positive (HBsAb+) PWH, who maintained HBsAb at 10 mIU/mL for at least 1 year after receiving three doses of the HBV vaccine. However, after immune stimulation with anti-CD3/CD28 antibodies, the frequency of cTfh cells in the non-HIV controls and HBsAb+ PWH increased, whereas the frequency of cTfh cells in the HBsAb− PWH tended to be more gradual. cTfh17-like and cTfh2-like cells, subsets of cTfh cells, are involved in humoral immunity, and PD-1 regulates the function of these cells in the germinal center. The frequencies of PD-1+ cTfh17-like and cTfh2-like cells at baseline did not differ significantly among the three groups. However, HBsAb− PWH had a lower frequency of PD-1+ cTfh17-like cells after immune stimulation than non-HIV controls did. The frequencies of PD-1+ cTfh17-like cells and cTfh2-like cells with high PD-1 expression were significantly lower in HBsAb− PWH than in non-HIV controls. Furthermore, the production of IL-21, which is essential for plasma cell differentiation, tended to be lower in HBsAb− PWH than in non-HIV controls or HBsAb+ PWH. Conclusions cTfh cells isolated from HBsAb− PWH may be unable to produce sufficient IL-21 after immune stimulation. This study is the first to suggest that cTfh cells may not function adequately in some PWH. This study highlights the need for large-scale validation of cTfh cell frequency and function in PWH. Clinical trial number Not applicable.