Tfh Cell Function Research Articles

The metabolic hormone leptin promotes the function of TFH cells and supports vaccine responses

Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.

PD-1 regulates affinity maturation of allergen-specific antibodies and severity of peanut allergy in mice

Abstract Programmed cell death-1 (PD-1), a member of the CD28 family, is critical for regulation of immune cell activation and maintenance of peripheral tolerance. Blocking antibodies against PD-1 have been used to sustain activation of T cells in cancer immunotherapy. T follicular helper (Tfh) cells play important role in the differentiation and maturation of antigen-specific B cells. Tfh cells highly and constitutively express PD-1; however, our knowledge is limited regarding the role of PD-1 in Tfh cell function and antibody response. We addressed this question by using a Tfh-dependent mouse model of peanut allergy. When naïve BALB/c mice were exposed to peanut flour by inhalation for 4 weeks, they developed peanut allergy as demonstrated by increased plasma levels of peanut-specific IgE and IgG antibodies and manifestation of acute anaphylaxis upon challenge with peanut extract. To examine the roles of PD-1, we administered a PD-1 blocking antibody to the animals during their exposure to peanut flour. Mice administered anti-PD-1 did not develop anaphylaxis even when they were challenged with peanut extract. Anti-PD1 treatment increased the number of Tfh cells and germinal center B cells in draining lymph nodes, and it increased plasma levels of peanut-specific IgG antibodies. Importantly, PD-1 blockade promoted the accumulation of low-affinity antibodies while it maintained the levels of high-affinity antibodies. These findings suggest that quality of allergen-specific antibodies affects the severity of allergic immune responses. Understanding the mechanisms that explain how PD-1 regulates the Tfh-B interaction and affinity maturation of antibodies likely leads to a better understanding of pathophysiology of allergic diseases.

Acquisition of optimal TFH cell function is defined by specific molecular, positional, and TCR dynamic signatures

The development of follicular helper CD4 T (TFH) cells is a dynamic process resulting in a heterogenous pool of TFH subsets. However, the cellular and molecular determinants of this heterogeneity and the possible mechanistic links between them is not clear. We found that human TFH differentiation is associated with significant changes in phenotypic, chemokine, functional, metabolic and transcriptional profile. Furthermore, this differentiation was associated with distinct positioning to follicular proliferating B cells. Single-cell T cell receptor (TCR) clonotype analysis indicated the transitioning toward PD-1hiCD57hi phenotype. Furthermore, the differentiation of TFH cells was associated with significant reduction in TCR level and drastic changes in immunological synapse formation. TFH synapse lacks a tight cSMAC (central supra molecular activation Cluster) but displays the TCR in peripheral microclusters, which are potentially advantageous in the ability of germinal center (GC) B cells to receive necessary help. Our data reveal significant aspects of human TFH heterogeneity and suggest that the PD-1hiCD57hi TFH cells, in particular, are endowed with distinctive programming and spatial positioning for optimal GC B cell help.

SLAMs Negatively Regulate IL-21 Production in Tfh-Like Cells from Allergic Rhinitis Patients.

BackgroundAllergic 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.MethodsCD4+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.ResultsThe 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.ConclusionSLAMs negatively regulate IL-21 production in CD4+CXCR5+ Tfh-like cells, which contributes to the pathogenesis of AR.

Frontiers of Autoantibodies in Autoimmune Disorders: Crosstalk Between Tfh/Tfr and Regulatory B Cells.

Balance of Tfh/Tfr cell is critically important for the maintenance of immune tolerance, as evidenced by the fact that T follicular helper (Tfh) cells are central to the autoantibodies generation through providing necessary help for germinal center (GC) B cells, whereas T follicular regulatory (Tfr) cells significantly inhibit autoimmune inflammation process through restraining Tfh cell responses. However, signals underlying the regulation of Tfh and Tfr cells are largely undefined. Regulatory B cells (Bregs) is a heterogeneous subpopulation of B cells with immunosuppressive function. Considerable advances have been made in their functions to produce anti‐inflammatory cytokines and to regulate Th17, Th1, and Treg cells in autoimmune diseases. The recent identification of their correlations with dysregulated Tfr/Tfh cells and autoantibody production makes Bregs an important checkpoint in GC response. Bregs exert profound impacts on the differentiation, function, and distribution of Tfh and Tfr cells in the immune microenvironment. Thus, unraveling mechanistic information on Tfh-Breg and Tfr-Breg interactions will inspire novel implications for the establishment of homeostasis and prevention of autoantibodies in diverse diseases. This review summarizes the dysregulation of Tfh/Tfr cells in autoimmune diseases with a focus on the emerging role of Bregs in regulating the balance between Tfh and Tfr cells. The previously unsuspected crosstalk between Bregs and Tfh/Tfr cells will be beneficial to understand the cellular mechanisms of autoantibody production and evoke a revolution in immunotherapy for autoimmune diseases.

The direct and indirect regulation of follicular T helper cell differentiation in inflammation and cancer.

Follicular T helper (Tfh) cells play important roles in facilitating B-cell differentiation and inducing the antibody response in humoral immunity and immune-associated inflammatory diseases, including infections, autoimmune diseases, and cancers. However, Tfh cell differentiation is mainly achieved through self-directed differentiation regulation and the indirect regulation mechanism of antigen-presenting cells (APCs). During the direct intrinsic differentiation of naïve CD4+ T cells into Tfh cells, Bcl-6, as the characteristic transcription factor, plays the core role of transcriptional regulation. APCs indirectly drive Tfh cell differentiation mainly by changing cytokine secretion mechanisms. Altered metabolic signaling is also critically involved in Tfh cell differentiation. This review summarizes the recent progress in understanding the direct and indirect regulatory signals and metabolic mechanisms of Tfh cell differentiation and function in immune-associated diseases.

Follicular helper T cells and follicular regulatory T cells in the immunopathology of primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease, characterized by lymphocytic infiltration into exocrine glands, which causes dry eyes, dry mouth, and systemic damage. Although the precise etiology of pSS is not clear yet, highly activated B cells, abundant anti-SSA/Ro, and anti-SSB/La autoantibodies are the hallmarks of this disease. Follicular helper T cells (Tfh), a subset of CD4+ T cells, with cell surface receptors PD-1 and CXCR5, express ICOS, transcription factor Bcl-6, and a cytokine IL-21. These cells help in the differentiation of B cells into plasma cells and stimulate the formation of germinal center (GC). Previous studies have demonstrated abundant Tfh cells in the peripheral blood and salivary glands (SGs) of the patients with pSS, correlated with extensive lymphocytic infiltration of the SGs and high disease activity scores. Patients with pSS who are treated with abatacept (CTLA-4 Ig) show fewer circulating Tfh cells, reduced expression of ICOS, and lower disease activity scores. Recently identified follicular regulatory T (Tfr) cells, a subset of regulatory T cells, control the function of Tfh cells and the GC reactions. Here, we summarize the observed alterations in Tfh and Tfr cell numbers, activation state, and circulating subset distribution in pSS. Our goal is to improve the understanding of the roles of Tfh and Tfr cells (surface marker expression, cytokine production, and transcription factors) in the pathogenesis of pSS, thus contributing to the identification of candidate therapeutic agents for this disease.

IL-2 contributes to cirrhosis-associated immune dysfunction by impairing follicular T helper cells in advanced cirrhosis

Patients with decompensated cirrhosis suffer from recurrent infections and inadequate responses to prophylactic vaccinations. However, many patients present with hypergammaglobulinemia (HGG), indicating a sustained ability to generate antibody responses. As follicular T helper (Tfh) cells are central facilitators of humoral immunity, we hypothesized that Tfh cell responses may be altered in advanced liver disease and we aimed to identify the mechanisms underlying any such alterations. Tfh, regulatory T (Treg) cells, B cells, circulating cytokines and immunoglobulins were analyzed in cohorts of patients with compensated (n= 37) and decompensated cirrhosis (n= 82) and in non-cirrhotic controls (n= 45). Intrahepatic T cells were analyzed in 8 decompensated patients. The influence of IL-2 on Tfh cell function was evaluated invitro, including Tfh cell cloning and T cell-B cell co-cultures with clones and primary tonsil-derived Tfh cells. Tfh cell frequencies were reduced in patients with decompensated cirrhosis, with phenotypic signatures indicative of increased IL-2 signaling. Soluble IL-2 receptor (sCD25) was elevated in these patients and CD4 T cells were more responsive to IL-2 signaling, as characterized by STAT5 phosphorylation. IL-2 exposure invitro diminished the Tfh phenotype and resulted in impaired Tfh helper function in co-culture experiments with naïve B cells. Tfh cells were barely detectable in cirrhotic livers. IL-2 signatures on Tfh cells in decompensated patients correlated with immunoglobulin levels, which were found to be associated with improved survival. Tfh cell impairment represents a previously underestimated feature of cirrhosis-associated immune dysfunction that is driven by IL-2. The presence of HGG in decompensated patients predicts an intact Tfh cell compartment and is associated with a favorable outcome. Patients with advanced cirrhosis often fail to generate protective immunity after prophylactic vaccinations and suffer from recurring infections that are associated with high mortality. Follicular T helper (Tfh) cells are specialized CD4 T cells that enable the emergence of antibody responses against microbial pathogens. This report demonstrates that Tfh cells are impaired in patients with advanced cirrhosis due to interleukin-2 signaling, a cytokine that is known to impair the generation of Tfh cells.

Continued Bcl6 Expression Prevents the Transdifferentiation of Established Tfh Cells into Th1 Cells during Acute Viral Infection

T follicular helper (Tfh) cells are crucial for the establishment of germinal centers (GCs) and potent antibody responses. Nevertheless, the Tcell-intrinsic factors that are required for the maintenance of already-established Tfh cells and GCs remain largely unknown. Here, we use temporally guided gene ablation in CD4+ Tcells to dissect the contributions of the Tfh-associated chemokine receptor CXCR5 and the transcription factor Bcl6. Induced ablation of Cxcr5 has minor effects on the function of established Tfh cells, and Cxcr5-ablated cells still exhibit most of the features of CXCR5+ Tfh cells. In contrast, continued Bcl6 expression is critical to maintain the GC Tfh cell phenotype and also the GC reaction. Importantly, Bcl6 ablation during acute viral infection results in the transdifferentiation of established Tfh into Th1 cells, thus highlighting the plasticity of Tfh cells. These findings have implications for strategies that boost or restrain Tfh cells and GCs in health and disease.

Dysregulation in B‐cell responses and T follicular helper cell function in ADA2 deficiency patients

Adenosine deaminase 2 deficiency (DADA2) is an autoinflammatory disease characterized by inflammatory vasculopathy, early strokes associated often with hypogammaglobulinemia. Pure red cell aplasia, thrombocytopenia, and neutropenia have been reported. The defect is due to biallelic loss of function of ADA2 gene, coding for a protein known to regulate the catabolism of extracellular adenosine. We therefore investigated immune phenotype and B- and T-cell responses in 14 DADA2 patients to address if ADA2 mutation affects B- and T-cell function. Here, we show a significant decrease in memory Bcells, in particular class switch memory, and an expansion of CD21low Bcells in DADA2 patients. In vitro stimulated B lymphocytes were able to secrete nonfunctional ADA2 protein, suggesting a cell intrinsic defect resulting in an impairment of B-cell proliferation and differentiation. Moreover, CD4+ and CD8+ Tcells were diminished; however, the frequency of circulating T follicular helper cells was significantly increased but they had an impairment in IL-21 production possibly contributing to an impaired Bcell help. Our findings suggest that ADA2 mutation could lead to a B-cell intrinsic defect but also to a defective Tfh cell function, which could contribute to the immunodeficient phenotype reported in DADA2 patients.

An imbalance between blood CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+Tfh cells may contribute to the immunopathogenesis of rheumatoid arthritis

BackgroundFollicular helper T (Tfh) cells are a subgroup of activated CD4+ T cells which can assist the formation and maintenance of germinal centers. Follicular regulatory T (Tfr) cells are a new class of regulatory T cells which play a major role in suppressing cells in humoral immunity. In contrast to the role of Tfh cells, Tfr cells can inhibit the function of Tfh cells and B cells. Imbalance of blood Tfr/Tfh ratio resulted in the expansion of auto-reactive B cells and auto-antibody production (). However, the effect of Tfr cells and Tfh cells in the pathogenesis of RA (rheumatoid arthritis) is unclear. The purpose of this study was to investigate the function of Tfr cells and Tfh cells in the pathogenesis of RA. MethodsWe recruited 20 patients fulfilled the the American College of Rheumatology diagnosis criteria and 20 healthy controls (HCs). The number of CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+ Tfh cells in 20 RA patients were measured by flow cytometry analysis. Furthermore, the correlations between the Tfr/Tfh ratio and the characteristic clinical parameters were assessed. The serum levels of IL-21(interleukin-21), CXCL13 (chemokine (C-X-C motif) ligand 13) and TGF-β (Transforming growth factor-β) were measured by ELISA. The formation of ectopic germinal center (GC) of synovial membrane was examined by H&E staining. The transcriptional levels of CXCR5 (C-X-C chemokine receptor type 5), CXCL13, ICOS (inducible co-stimulater) and TGF-β mRNA were also analyzed. In addition, the expression of Bcl-6 (B-cell lymphoma 6), CXCR5, CXCL13 and ICOS in synovial membrane were examined by immunohistochemistry. ResultsRA patients had more Tfh cells in peripheral blood, conversely, the frequency of blood Tfr cells (p < 0.05) and the ratio of Tfr/Tfh were significantly decreased compared to healthy controls (p < 0.05, p < 0.01). Furthermore, the ratio of Tfr/Tfh was negatively correlated with values of ESR (r=-0.57, p < 0.05), RF (r=-0.5275, p < 0.001), CRP (r=-0.4486, p < 0.001), IgG (r=-0.4631, p < 0.05), DAS28 scores (r=-0.5645, p < 0.01), as well as the levels of IL-21(r=-0.7398, p < 0.01), CXCL13 (r=-0.4832, p < 0.05). However, the ratio of Tfr/Tfh was positively with the serum level of TGF-β (r=0.5115, p < 0.05). Higher mRNA expression of CXCR5, CXCL13, ICOS and lower TGF-β mRNA expression were observed in RA patients. The serum expression level of IL-21, CXCL13 was significantly increased and expression of TGF-β was significantly decreased in RA patients. Furthermore, ectopic germinal center formation and higher expression of Bcl-6, CXCR5, ICOS, CXCL13 in the synovial membrane of the joints in RA patients were observed. ConclusionsThe decreased blood CD4+CXCR5+Foxp3+ Tfr cells/CD4+CXCR5+ Tfhcells may be responsible for the immunopathogenesis of RA.

Evaluation of T Follicular Helper Cells and Germinal Center Response During Influenza A Virus Infection in Mice.

T Follicular Helper (Tfh) cells are an independent CD4+T cell subset specialized in providing help for germinal center (GC) development and generation of high-affinity antibodies. In influenza virus infection, robust Tfh and GC B cell responses are induced to facilitate effective virus eradication, which confers a qualified mouse model for Tfh-associated study. In this paper, we described protocols in detection of basic Tfh-associated immune response during influenza virus infection in mice. These protocols include: intranasal inoculation of influenza virus; flow cytometry staining and analysis of polyclonal and antigen-specific Tfh cells, GC B cells and plasma cells; immunofluorescence detection of GCs; enzyme-linked immunosorbent assay (ELISA) of influenza virus-specific antibody in serum. These assays basically quantify the differentiation and function of Tfh cells in influenza virus infection, thus providing help for studies in elucidating differentiation mechanism and manipulation strategy.

Regulatory Effect of Sishen Pill on Tfh Cells in Mice With Experimental Colitis.

The T follicular helper T (Tfh) cells play a significant role in the pathogenesis of inflammatory bowel disease (IBD), which is regulated by the Bcl-6/Blimp-1 pathway. Some studies have suggested that regulating activation of the Bcl-6/Blimp-1 pathway should be an effective method to treat IBD. Sishen Pill (SSP) has been used frequently to treat chronic colitis. Its mechanism is related to the downstream proteins in the Bcl-6/Blimp-1 pathway. However, it is unknown whether SSP regulates the function and differentiation of Tfh cells to treat IBD. In the present study, chronic colitis was induced by dextran sodium sulfate and treated with SSP for 7 days. SSP effectively treated chronic colitis, regulated the balance between Tfh10, Tfh17 and T follicular regulatory cells, while SSP increased the Blimp-1 level, inhibited expressions of Bcl-6, T-cell costimulator, programmed death (PD)-1 and PD-ligand 1 on the surface of Tfh cells. SSP inhibited activation of BcL-6, phosphorylated signal transducer and activator of transcription (p-STAT)3, signal lymphocyte activation molecule (SLAM)-associated protein but improved Blimp-1 and STAT3 expression in colonic tissues. The results indicated that SSP regulated the differentiation and function of Tfh cells to treat IBD, which was potentially related with inhibiting the Bcl-6/Blimp-1 pathway.

Imbalance in T follicular helper cells producing IL-17 promotes pro-inflammatory responses in MuSK antibody positive myasthenia gravis

A detailed understanding of the role of Tfh cells in MuSK-antibody positive myasthenia gravis (MuSK-MG) is lacking. We characterized phenotype and function of Tfh cells in MuSK-MG patients and controls. We found similar overall Tfh and follicular regulatory (Tfr) T cell frequencies in MuSK-MG and healthy controls, but MuSK-MG patients exhibited higher frequencies of Tfh17 cells and a higher ratio of Tfh:Tfr cells. These results suggest imbalanced Tfh cell regulation, further supported by increased frequencies of CD4 T cells co-producing IL-21/IL-17 and IL-17/IFN-γ, and increased Tfh-supported IgG production. These results support a role for Tfh cell dysregulation in MuSK-MG immunopathology.

T Follicular Helper Cells Regulate Humoral Response for Host Protection against Intestinal Citrobacter rodentium Infection.

Citrobacter rodentium colonizes at the colon and causes mucosal inflammation in mice. Previous studies have revealed the importance of the innate and adaptive immune response for controlling C. rodentium infection. In the present study, we examined the role of T follicular helper (Tfh) cells in intestinal C. rodentium infection using mice with Bcl6 deficiency in T cells. Tfh cells were absolutely required at the late, but not the early, phase to control infection. Compared with control mice, we observed systemic pathogen dissemination and more severe colitis in Tfh-deficient mice. Furthermore, the susceptibility of Tfh-deficient mice correlated with an impaired serum IgG1 response to infection, and serum Abs from infected wild-type mice protected Tfh-deficient mice from infection. The transfer of wild-type Tfh cells also restored the levels of IgG1 and led to effective clearance of the pathogens in Tfh-deficient mice. Moreover, during C. rodentium infection, IL-21- and IL-4-producing Tfh cells were increased obviously in wild-type mice, correlating with IgG1 as the major isotype in germinal center B cells. Taken together, our work highlights the requirement and the function of Tfh cells in regulating humoral response for the host protection against C. rodentium infection.

Bcl6 is the nexus transcription factor of T follicular helper cell (TFH) differentiation via a set of repressor-of-repressor gene circuits

Abstract T follicular helper (TFH) cells are a distinct type of CD4 T cells that are essential for most antibody and B lymphocyte responses. TFH regulation and dysregulation is involved in a range of diseases. Bcl6 is the lineage defining transcription factor of TFH cells and its activity is essential for TFH cell differentiation and function. However, how Bcl6 controls TFH biology has largely remained unclear, at least in part due to intrinsic challenges of connecting repressors to gene upregulation in complex cell types with multiple possible differentiation fates. Multiple competing models were tested here by a series of experimental approaches. We ruled out the model that TFH is a default pathway of CD4 T cell by utilizing Bcl6 and Blimp1 double deficient mice in acute virus infection and protein immunization. We showed that Bcl6 has a strong negative autoregulatory loop in TFH cells, by generating mice containing a deletion mutation of an 8-nucleotide Bcl6 binding site in the Bcl6 promoter. To determine putative Bcl6 target TFs, we developed an integrated analytic approach using RNA-seq, BCL6 ChIP-seq, and ATAC-seq data and Bcl6 and Blimp1 double KO mice. Using this approach, Runx2, Runx3, and Klf2 were identified as Bcl6-targeted repressors (Bcl6-r TFs) that regulate important TFH genes. Taken together, Bcl6 controls pleiotropic attributes of TFH differentiation and function (migration, costimulation, inhibitory receptors, and cytokines) via multiple repressor-of-repressor gene circuits.

Follicular helper T cells express a metabolic and cell signaling gene signature in a lupus-prone murine model

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoreactive follicular helper T (Tfh) cells license high-affinity autoantibody production. Strikingly, the frequency of circulating Tfh is correlated with disease activity in SLE patients. As such, understanding the molecular mechanisms responsible for the aberrant Tfh cell generation and activation in lupus is of fundamental significance. We previously demonstrated that expanded Tfh cells in the B6.Sle1.Sle2.Sle3 (TC for triple congenic) lupus model exhibit high glycolysis and oxidative metabolism, which can be constrained by inhibiting glycolysis with 2-deoxyglucose (2DG). We performed RNA-seq analyses of splenic Tfh and naïve CD4+ T cells (Tn) comparing between TC and B6 mice. First, data revealed a large number of shared gene signatures in Tfh and Tn comparing between TC and B6 group, implicating that the aberrant development of Tfh initiates as early as Tn state. Further alignment of the Tfh transcriptome obtained from RNA-seq and earlier microarray assays demonstrated concerted alterations in numerous gene signatures of overactivation of T cells including dysregulated tyrosine kinase signaling and MAPK signaling pathways. Gene set enrichment analyses (GSEA) further revealed altered metabolic pathways (e.g., oxidative phosphorylation and pyruvate metabolism) among splenic TC Tfh cells. Finally, we demonstrated that 2-DG partially correct the aberrant expression patterns in TC splenic Tfh cells, restoring oxidative phosphorylation and the MAPK pathways. Since 2DG eliminates the expansion of autoreactive TFh cells, these results suggest that these two pathways may be critical to lupus Tfh cell function.

1IFN-α Modulates Memory Tfh Cells and Memory B Cells in Mice, Following Recombinant FMDV Adenoviral Challenge.

Follicular helper T (Tfh) cells regulate high-affinity antibody production. Some findings have indicated that Tfh cells could be differentiated into memory cells. Here we have investigated the effects of IFN-α, as an adjuvant, on the generation of memory Tfh cell and memory B cell responses. The data showed that adenoviral vectors expressing: (i) foot-and-mouth disease virus (FMDV) VP1 proteins and porcine IFN-α, or (ii) porcine IFN-α alone, potently enhanced the generation of memory Tfh cells, especially the CCR7lo memory Tfh subset. Upon rechallenge with FMD recombinant adenoviral vaccines, IFN-α enhances Tfh cells activity, rapidly upregulating their signature Bcl-6, CXCR5, and IL-21 markers. The results suggest that IFN-α enhances the levels of the transcription factor Bcl-6 within Tfh cells, potentially by regulating STAT1. Additionally, IFN-α substantially increased the number of IgG1+ and CD86+ memory B cells, which are responsible for inducing the rapid effector functions of memory Tfh cells after vaccine reactivation, establishing the close relationship between memory B cell and memory Tfh cell subsets. In brief, IFN-α enhances the potency of FMD recombinant adenoviral vaccines to induce memory Tfh and memory B cell responses, thus elevating serum antibody titers. IFN-α administration therefore represents an attractive strategy for enhancing responses to vaccination.

Antagonizing miR-7 suppresses B cell hyperresponsiveness and inhibits lupus development

ObjectivesThe objective of this study was to address the biological function of miR-7 in an animal model of systemic lupus erythematosus. MethodsMRLlpr/lpr lupus mice were administrated antagomiR-7 or a scramble control by tail vein for 5weeks. Three groups of animals’ tissues were assessed for lupus manifestations by immunofluorescence and immunohistochemistry, and serum was examined for levels of autoantibodies and inflammatory cytokines. Splenic B cell subsets were assessed for intracellular expression of PI3K signaling by FACS. Finally, the ability of the miR-7 antagomir to regulate the expansion of T follicular helper (Tfh) cells and B cell hyperresponsiveness was further explored. ResultsWe found that miR-7 was up-regulated in MRLlpr/lpr lupus mice and directly targeted PTEN mRNA in B cells. Up-regulated miR-7 in MRLlpr/lpr lupus B cells was negatively correlated with PTEN expression. Notably, miR-7 antagomir treatment reduced lupus manifestations in MRLlpr/lpr lupus mice. miR-7-mediated down-regulation of PTEN/AKT signaling promoted B cell differentiation into plasmablasts/plasma cells and spontaneous germinal center (GC) formation, whereas miR-7 antagomir normalized splenic B cell subtypes. Besides suppressing the activation of B cells, miR-7 antagomir intervention also down-regulated STAT3 phosphorylation and production of IL-21 and reduced Tfh expansion. ConclusionThe above data have demonstrated the critical roles of miR-7 not only in regulating PTEN expression and also B cell and Tfh cell function in lupus-prone MRLlpr/lpr lupus mice. Furthermore, the disease manifestations in MRLlpr/lpr lupus mice are efficiently improved by miR-7 antagomir, indicating miR-7 as a potential treatment strategy in SLE.

Functions of Tfh Cells in Common Variable Immunodeficiency.

Common variable immunodeficiency is the most common clinical primary immunodeficiency in adults. Its hallmarks are hypogammaglobulinemia and compromised B-cell differentiation into memory or antibody-secreting cells leading to recurrent infections. This disease is heterogeneous, with some patients harboring multiple complications such as lymphoproliferative disorders, autoimmune manifestations, or granulomatous inflammation. The mechanisms leading to these complications remain elusive despite numerous associations found in the literature. For instance, although described as a B cell intrinsic disease, numerous abnormalities have been reported in other immune cell compartments. Here, we tuned our attention to follicular helper T cells, a CD4+ T cell population specialized in B cell help, considering the recent publications showing an involvement of these cells in CVID pathogenesis.