Function Of Follicular Helper Research Articles

Id1 expression in CD4 T cells promotes differentiation and function of follicular helper T cells and upregulation of related functional molecules.

Although the roles of E proteins and inhibitors of DNA-binding (Id) in T follicular helper (TFH) and T follicular regulatory (TFR) cells have been previously reported, direct models demonstrating the impact of multiple E protein members have been lacking. To suppress all E proteins including E2A, HEB and E2-2, we overexpressed Id1 in CD4 cells using a CD4-Id1 mouse model, to observe any changes in TFH and TFR cell differentiation. Our objective was to gain better understanding of the roles that E proteins and Id molecules play in the differentiation of TFH and TFR cells. The CD4-Id1 transgenic (TG) mice that we constructed overexpressed Id1 in CD4 cells, inhibiting E protein function. Our results showed an increase in the proportion and absolute numbers of Treg, TFH and TFR cells in the spleen of TG mice. Additionally, the expression of surface characterisation molecules PD-1 and ICOS was significantly upregulated in TFH and TFR cells. The study also revealed a downregulation of the marginal zone B cell precursor and an increase in the activation and secretion of IgG1 in spleen B cells. Furthermore, the peripheral TFH cells of TG mice enhanced the function of assisting B cells. RNA sequencing results indicated that a variety of TFH-related functional molecules were upregulated in TFH cells of Id1 TG mice. In conclusion, E proteins play a crucial role in regulating TFH/TFR cell differentiation and function and suppressing E protein activity promotes germinal centre humoral immunity, which has important implications for immune regulation and treating related diseases.

Retracted: The Effect of miR-138 on the Function of Follicular Helper T Cells and the Differentiation of B Cells in Osteosarcoma.

[This retracts the article DOI: 10.1155/2021/2057782.].

The Effect of miR-138 on the Function of Follicular Helper T Cells and the Differentiation of B Cells in Osteosarcoma.

Objective To explore the effect of miR-138 on the function of follicular helper T (Tfh) cells and the differentiation of B cells in osteosarcoma. Methods Clinically collect peripheral blood from osteosarcoma (OS) patients and healthy volunteers (HC), as well as OS tumor tissues (OS tumor) and adjacent tissues with normal histology (normal group). The CD4+CXCR5+Tfh cells of OS patients were screened and isolated by flow cytometry, and the expression of Tfh cell membrane surface antigens PD-1 and CTLA-4 was detected. In addition, qRT-PCR was used to detect the expression of miR-138 in tissues and Tfh cells, and the correlation relationship between miR-138 and PD-1 and CTLA-4 was analyzed. After interference or overexpression of miR-138 in Tfh cells, coculture with untreated B cells was done, and the levels of IL-10, IL-12, IL-21, and INF-γ in Tfh cell culture medium and the levels of IgM, IgG, and IgA in B cell culture medium after coculture were measured by ELISA. Flow cytometry was used to detect the expression of B cell membrane surface antigens CD27 and CD38 after coculture. Results The rate of PD-1- and CTLA-4 positive cells in the peripheral blood and tissues of the OS group was significantly increased, the expression of miR-138 was significantly reduced, and the expression of miR-138 was negatively correlated with the expression of PD-1 and CTLA-4. In addition, upregulation of miR-138 can lead to a significant increase in the level of IL-10 in the supernatant of Tfh cells and a significant decrease in the levels of IL-12, IL-21, and INF-γ, which in turn leads to increased levels of IgM, IgG, and IgA released by B cells. At the same time, it significantly increases the rate of CD27- and CD38-positive cells and promotes the maturation of B cells. Downregulating miR-138 has the opposite effect. Conclusion Downregulating the expression of miR-138 in osteosarcoma can improve the dysfunction of CD4+CXCR5+Tfh cells and promote the differentiation of B cells.

Immune mechanisms involved in the coexistence of oral lichen planus and autoimmune thyroid diseases.

Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disease with unclear etiology. Autoimmune thyroid diseases (AITD) is a type of autoimmune disease characterized by increased thyroid-specific antibodies. In recent years, more and more studies have found that the incidence of AITD is increased in OLP patients. The occurrence and development of OLP and AITD may be related to the expression of thyroid autoantigen in oral keratinocytes, the imbalance of thyroid hormone （Th）1/Th2 and Th17/Treg cell subsets, the abnormal quantity and function of follicular helper T cells and chemokines and the specific killing ability of CD8 T cells to target cells. In this article, the possible immune mechanisms involved in the coexistence of OLP and AITD are reviewed to provide insights for the diagnosis, treatment and prevention of these two diseases from the perspective of immunology.

Foxo3 Promotes the Differentiation and Function of Follicular Helper T Cells

Follicular helper Tcells (Tfhs) are essential for germinal center (GC) B cell maturation and antibody development. However, the intrinsic mechanisms that regulate Tfh differentiation are largely unknown. Here, we demonstrate that the frequencies of Tfhs and GC B cells, as well as interleukin-21 (IL-21) and anti-ovalbumin (OVA) antibodies, are markedly decreased in forkhead box O3 (Foxo3) knockout mice immunized with OVA. Using mixed bone marrow chimeras and lymphocyte-repopulated Rag1-/- mice proves that wild-type (WT), but not Foxo3-deficient Tcells provoke GC B cell maturation and antibody production. Deficiency of Foxo3 inhibits inducible Tcell co-stimulator (ICOS)-induced Tfh differentiation. Chromatin immunoprecipitation assay results suggest that Foxo3 is able to bind to the IL-21 promoter and regulate IL-21 secretion. In conclusion, our study unveils a critical role of Foxo3 in the regulation of Tfh differentiation and IL-21 production. Modulating Foxo3 activity may be beneficial for enhancing or preventing antibody-mediated immune responses.

A role for antibodies in natural HIV control.

Rare patients naturally control HIV replication without antiretroviral therapy. Understanding the mechanisms implicated in natural HIV control will inform the development of immunotherapies against HIV. Elite controllers are known for developing efficient antiviral T-cell responses, but recent findings suggest that antibody responses also play a significant role in HIV control. We review the key studies that uncovered a potent memory B-cell response and highly functional anti-HIV antibodies in elite controllers, and explore the mechanisms that may account for the distinct properties of their humoral response. Elite controllers maintain a large HIV-specific memory B-cell pool that is sustained by efficient T follicular helper function. Neutralizing antibody rarely show high titers in controllers, but seem capable, at least in certain cases, of neutralizing contemporaneous viral strains. In addition, elite controllers display a unique HIV-specific antibody profile in terms of isotype, antigen specificity, and glycosylation pattern, resulting in polyfunctional antibody effector functions that may promote infected cell lysis and prime effectors of the antiviral immune response. Lessons from elite controller studies argue for the importance of integrating the many parameters defining a polyfunctional antibody response when evaluating candidate vaccines and immunotherapeutic approaches directed at HIV.

Aberrant Expansion and Function of Follicular Helper T Cell Subsets in IgG4-Related Disease.

ObjectiveTo determine the number and function of follicular helper T (Tfh) cell subsets in IgG4‐related disease (IgG4‐RD).MethodsMononuclear cells from the peripheral blood and involved tissue of patients with IgG4‐RD were assessed for Tfh cells and their subsets, and levels of B cell lymphoma 6 (Bcl‐6), B lymphocyte–induced maturation protein 1 (BLIMP‐1), and interleukin‐21 (IL‐21) messenger RNA (mRNA). Immunohistochemical and immunofluorescence techniques were used to assess the involved tissue of patients to determine the location of IL‐21, Bcl‐6, and CD4+CXCR5+ Tfh cells. Furthermore, the ability of circulating Tfh (cTfh) cell subsets to induce B cell proliferation, apoptosis, and differentiation and to produce IgG4 was explored in cell cocultures in vitro.ResultsFrequencies of cTfh cells were significantly increased in the peripheral blood of patients with IgG4‐RD, and even higher frequencies were observed in the involved tissue. Percentages of programmed cell death protein 1 in CD4+CXCR5+ICOS+ cTfh cells were positively correlated with the serum levels of IgG and IgG4, IgG4:IgG ratio, number of involved organs, and frequency of CD19+CD24−CD38high plasmablasts/plasma cells. Levels of BLIMP‐1 and IL‐21 mRNA in peripheral CD4+ T cells were increased in patients with IgG4‐RD compared to healthy controls, and this was correlated with the levels of serum IgG4. Moreover, in the involved tissue, Bcl‐6, IL‐21, and Tfh cells were highly expressed. Compared to cTfh cells from healthy controls, cTfh cells from patients with IgG4‐RD could facilitate B cell proliferation and inhibit B cell apoptosis more efficiently, and enhanced the differentiation of naive B cells into switched memory B cells and plasmablasts/plasma cells, with a resultant increase in the secretion of IgG4. Notably, the cTfh1 and cTfh2 cell subsets were the most effective at providing B cell help.ConclusionTfh cell subsets are expanded in IgG4‐RD and may play pivotal roles in the pathogenesis of the disease.

Circulating follicular helper T cells exhibit reduced ICOS expression and impaired function in narcolepsy type 1 patients

Despite genetic and epidemiological evidence strongly supporting an autoimmune basis for narcolepsy type 1, the mechanisms involved have remained largely unknown. Here, we aimed to investigate whether the frequency and function of circulating follicular helper and follicular regulatory T cells are altered in narcolepsy type 1.Peripheral blood mononuclear cells were collected from 32 patients with narcolepsy type 1, including 11 who developed disease after Pandemrix® vaccination, and 32 age-, sex-, and HLA-DQB1*06:02-matched healthy individuals. The frequency and phenotype of the different circulating B cell and follicular T cell subsets were examined by flow cytometry. The function of follicular helper T cells was evaluated by assessing the differentiation of naïve and memory B cells in a co-culture assay.We revealed a notable increase in the frequency of circulating B cells and CD4+CXCR5+ follicular T cells in narcolepsy patients compared to age-, sex- and HLA-matched healthy controls. However, the inducible T-cell costimulator molecule, ICOS, was selectively down-regulated on follicular T cells from patients. Reduced frequency of activated ICOS+ and PD1high blood follicular T cells was also observed in the narcolepsy group. Importantly, follicular T cells isolated from patients with narcolepsy type 1 had a reduced capacity to drive the proliferation/survival and differentiation of memory B cells.Our results provide novel insights into the potential involvement of T cell-dependent B cell responses in the pathogenesis of narcolepsy type 1 in which down-regulation of ICOS expression on follicular helper T cells correlates with their reduced function. We hypothesize that these changes contribute to regulation of the deleterious autoimmune process after disease onset.

ICOS-mediated phosphoinositide 3-kinase signaling controls induction and maintenance of collagen-induced arthritis

Abstract The inducible T-cell costimulator (ICOS) is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS+ T cells in the synovial fluid suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS-mediated phosphoinositide 3-kinase (PI3K) signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, ICOS-mediated PI3K signaling was critical for antibody production and expansion of inflammatory T cells. Further, we found that ICOS-PI3K signaling is important for maintenance of CIA in an antibody independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA suggesting a potential link between ICOS-PI3K signaling and glucose metabolism. Thus, we identified ICOS-PI3K axis as a key signaling pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.

ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis.

ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS+ T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, the Tyr181-based SH2-binding motif of ICOS that is known to activate PI3K was critical for Ab production and expansion of inflammatory T cells. Furthermore, we found that Tyr181-dependent ICOS signaling is important for maintenance of CIA in an Ab-independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA, suggesting an overlap between ICOS signaling, PI3K signaling, and glucose metabolism. Thus, we identified ICOS as a key costimulatory pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.

Function of follicular helper T cell is impaired and correlates with survival time in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) represents one of the most common and aggressive cancers worldwide. The PD-1/PD-L1 interaction plays important roles in cancer immunology, and expression of PD-L1 has been discovered in NSCLC tumor cells. Since follicular helper T (Tfh) cells have characteristic high PD-1 expression, we therefore investigated the inflammatory status of Tfh in NSCLC. CD4+CXCR5+ T cell population was examined to define Tfh cells. Data showed that frequency of Tfh cells in peripheral blood was significantly lower in NSCLC patients than in healthy controls. In both primary and metastatic tumors, infiltration of Tfh cells was observed, suggesting that they participated in the antitumor immunity of NSCLC patients. Compared to other T cell subsets, the Tfh cells from the peripheral blood and the resected tumors of NSCLC patients presented elevated apoptosis and reduced proliferation capacity. The Tfh cells from NSCLC patients were also less effective at downregulating IgD and upregulating CD27 expression in naive B cells, and induced less IgM, IgG and IgA secretion, than those from healthy controls. We then found that the survival time from the date of surgery was positively correlated with the frequency of tumor-infiltrating Tfh cells in NSCLC subjects. Overall, the results from this study demonstrated that the Tfh cells were likely involved in the antitumor immunity and were associated with better clinical outcomes, but suffered strong immunosuppression in NSCLC. Enhancing the Tfh cell activity therefore represents a potential therapeutic strategy in NSCLC.

Development and function of follicular helper T cells.

Most currently available vaccines rely on the induction of long-lasting protective humoral immune responses by memory B cells and plasma cells. Antibody responses against most antigens require interactions between antigen-specific B cells and CD4(+) T cells. Follicular helper T cells (TFH cells) are specialized subset of T cells that provide help to B cells and are essential for germinal center formation, affinity maturation, and the development of high-affinity antibodies. TFH-cell differentiation is a multistage process involving B-cell lymphoma 6 and other transcription factors, cytokines, and costimulation through inducible costimulator (ICOS) and several other molecules. This article reviews recent advances in our understanding of TFH cell biology, including their differentiation, transcriptional regulation, and function.

Reduced T follicular helper function in aged mice is correlated with increased numbers of T regulatory cells (LYM2P.725)

Abstract T follicular helper (TFH) cells are critical for a germinal center response and a robust humoral response. Aging has a profound impact on the formation of a strong humoral/germinal center response, yet the impact of aging on TFH remains unclear. This study explores the effects of aging on TFH transcription factors, which could explain some of the age related germinal center defects. During influenza infection, young mice exhibit a very robust IgG response, which is significantly reduced in aged mice. Initial studies showed that there are no differences in the number of flu-specific TFH (CXCR5hi PD-1hi) during the course of the infection, as determined using MHC class II NP tetramer. To determine transcription factor expression and localization of TFH, we performed multicolor flow cytometry and confocal microscopy on spleens from these mice. There was no difference in BCL6 expression in young and aged flu-specific TFH. But, strikingly, flu-specific BCL6hi TFH from aged mice had increased co-expression of Foxp3, characteristic of T follicular regulatory cells, a critical controller of germinal center responses. We are currently exploring the contribution of whether the differences in TFH transcription factor expression are intrinsic to aged CD4+ T cells or are a result of the aged microenvironment. These results strongly suggest that aging has a dramatic impact on transcription factor expression in CD4 T cells, which can influence the establishment of a robust immune response.

S-4: Differentiation and function of follicular helper T cells (Tfh)

T cell help to B cells is a fundamental aspect of adaptive immunity and the generation of B cell memory. The development of virtually all neutralizing antibodies is CD4 T cell dependent. Tfh cells are the unique and specialized T cells for B cell help, required for development of germinal centers, affinity matured Abs, and most B cell memory (memory B cells and memory plasma cells (PC)). T cell help is frequently a primary limiting factor for these processes. Therefore understanding and controlling Tfh cells is important for developing true rational vaccine development strategies (Crotty, ARI 2011). Tfh cells are also potentially extremely useful biomarkers in human vaccine clinical trials. Tfh depend on expression of the transcription factor Bcl6, and there are multiple steps required for follicular helper T cell differentiation, including roles of IL-6, IL-21, and ICOS. Importantly, additional factors required for Tfh differentiation remain poorly defined. Tfh function is mediated in part by cytokines IL-21 and IL-4, as well as the chemokine CXCL13.

Control of TFH differentiation by a microRNA cluster

The generation of T cell–dependent humoral immunity is regulated by the miR-17∼92 cluster of microRNAs through their influence on the differentiation and function of follicular helper T cells.

Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated by distinct biochemical mechanisms

The transcription factor Bcl-6 orchestrates the germinal center reaction through its actions in B and T cells, and regulates inflammatory signaling in macrophages. We report that genetic replacement by mutant Bcl-6, which cannot bind corepressors to its BTB domain, disrupted germinal center formation and immunoglobulin affinity maturation, due to a defect in B cell proliferation and survival. In contrast, BTB loss of function had no effect on T follicular helper cell differentiation and function, nor other T helper subsets. Bcl6 null mice displayed a lethal inflammatory phenotype, whereas BTB mutant mice experienced normal healthy lives with no inflammation. Bcl-6 repression of inflammatory responses in macrophages was accordingly independent of the BTB domain repressor function. Bcl-6 thus mediates its actions through lineage-specific biochemical functions.

The development and function of follicular helper T cells in immune responses

Follicular helper T cells (Tfh) have been referred as a lineage that provides a help for B cells to proliferate and undergo antibody affinity maturation in the germinal center. Evidence has supported that Tfh subset development, like other lineages, is dependent on microenvironment where a particular transcriptional program is initiated. It has been shown that Bcl-6 and IL-21 act as master regulators for the development and function of Tfh cells. Tfh dysregulation is involved in the development of autoimmune pathologies, such as systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases. The present review highlights the recent advances in the field of Tfh cells and focus on their development and function.

Follicular Helper NKT Cells Induce Limited B Cell Responses and Germinal Center Formation in the Absence of CD4+ T Cell Help

B cells require MHC class II (MHC II)-restricted cognate help and CD40 engagement by CD4(+) T follicular helper (T(FH)) cells to form germinal centers and long-lasting Ab responses. Invariant NKT (iNKT) cells are innate-like lymphocytes that jumpstart the adaptive immune response when activated by the CD1d-restricted lipid α-galactosylceramide (αGalCer). We previously observed that immunization of mice lacking CD4(+) T cells (MHC II(-/-)) elicits specific IgG responses only when protein Ags are mixed with αGalCer. In this study, we investigated the mechanisms underpinning this observation. We find that induction of Ag-specific Ab responses in MHC II(-/-) mice upon immunization with protein Ags mixed with αGalCer requires CD1d expression and CD40 engagement on B cells, suggesting that iNKT cells provide CD1d-restricted cognate help for B cells. Remarkably, splenic iNKT cells from immunized MHC II(-/-) mice display a typical CXCR5(hi)programmed death-1(hi)ICOS(hi)Bcl-6(hi) T(FH) phenotype and induce germinal centers. The specific IgG response induced in MHC II(-/-) mice has shorter duration than that developing in CD4-competent animals, suggesting that iNKT(FH) cells preferentially induce transient rather than long-lived Ab responses. Together, these results suggest that iNKT cells can be co-opted into the follicular helper function, yet iNKT(FH) and CD4(+) T(FH) cells display distinct helper features, consistent with the notion that these two cell subsets play nonredundant functions throughout immune responses.

A BATF-ling connection between B cells and follicular helper T cells

The transcription factor BATF directly regulates key components of the formation and function of follicular helper T cells and antibody class switching in B cells.

Addendum: The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding

Addendum: The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding