scholarly journals Transient T-bet expression functionally specifies a distinct T follicular helper subset

2018 ◽  
Vol 215 (11) ◽  
pp. 2705-2714 ◽  
Author(s):  
Difeng Fang ◽  
Kairong Cui ◽  
Kairui Mao ◽  
Gangqing Hu ◽  
Rao Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Subset ◽  
Tissue Imaging ◽  
Mouse Strains ◽  
Tfh Cells ◽  
Follicular Helper ◽  
History Of ◽  
Ifn Γ ◽  
Almost All

T follicular helper (Tfh) cells express transcription factor BCL-6 and cytokine IL-21. Mature Tfh cells are also capable of producing IFN-γ without expressing the Th1 transcription factor T-bet. Whether this IFN-γ–producing Tfh population represents a unique Tfh subset with a distinct differentiation pathway is poorly understood. By using T-bet fate–mapping mouse strains, we discovered that almost all the IFN-γ–producing Tfh cells have previously expressed T-bet and express high levels of NKG2D. DNase I hypersensitivity analysis indicated that the Ifng gene locus is partially accessible in this “ex–T-bet” population with a history of T-bet expression. Furthermore, multicolor tissue imaging revealed that the ex–T-bet Tfh cells found in germinal centers express IFN-γ in situ. Finally, we found that IFN-γ–expressing Tfh cells are absent in T-bet–deficient mice, but fully present in mice with T-bet deletion at late stages of T cell differentiation. Together, our findings demonstrate that transient expression of T-bet epigenetically imprints the Ifng locus for cytokine production in this Th1-like Tfh cell subset.

scholarly journals Explaining the ocean's richest biodiversity hotspot and global patterns of fish diversity

2018 ◽  
Vol 285 (1888) ◽  
pp. 20181314 ◽  
Author(s):  
Elizabeth Christina Miller ◽  
Kenji T. Hayashi ◽  
Dongyuan Song ◽  
John J. Wiens
Keyword(s):  
Large Scale ◽  
Fish Diversity ◽  
Relative Importance ◽  
Diversification Rates ◽  
Marine Habitats ◽  
History Of ◽  
Richness Patterns ◽  
Colonization Time ◽  
Almost All

For most marine organisms, species richness peaks in the Central Indo-Pacific region and declines longitudinally, a striking pattern that remains poorly understood. Here, we used phylogenetic approaches to address the causes of richness patterns among global marine regions, comparing the relative importance of colonization time, number of colonization events, and diversification rates (speciation minus extinction). We estimated regional richness using distributional data for almost all percomorph fishes (17 435 species total, including approximately 72% of all marine fishes and approximately 33% of all freshwater fishes). The high diversity of the Central Indo-Pacific was explained by its colonization by many lineages 5.3–34 million years ago. These relatively old colonizations allowed more time for richness to build up through in situ diversification compared to other warm-marine regions. Surprisingly, diversification rates were decoupled from marine richness patterns, with clades in low-richness cold-marine habitats having the highest rates. Unlike marine richness, freshwater diversity was largely derived from a few ancient colonizations, coupled with high diversification rates. Our results are congruent with the geological history of the marine tropics, and thus may apply to many other organisms. Beyond marine biogeography, we add to the growing number of cases where colonization and time-for-speciation explain large-scale richness patterns instead of diversification rates.

scholarly journals Increased Frequency of Circulating Follicular Helper T Cells in Patients with Rheumatoid Arthritis

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Jie Ma ◽  
Chenlu Zhu ◽  
Bin Ma ◽  
Jie Tian ◽  
Samuel Essien Baidoo ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Activation ◽  
Critical Role ◽  
Cell Subset ◽  
Antibody Responses ◽  
Helper T Cells ◽  
B Cell Activation ◽  
Cell Frequency ◽  
Tfh Cells ◽  
Follicular Helper

Follicular helper T (Tfh) cells are recognized as a distinct CD4+helper T-cell subset, which provides for B-cell activation and production of specific antibody responses, and play a critical role in the development of autoimmune disease. So far, only one study investigated the circulating Tfh cells increased in a subset of SLE patients. Since relatively little is known about the Tfh cells in rheumatoid arthritis (RA) patients, in this study, Tfh-cell frequency, related cytokine IL-21, and transcription factor Bcl-6 were investigated in 53 patients with RA and 31 health controls. Firstly, we found that the frequency ofCD4+CXCR5+ICOShighTfh cells was increased significantly in the peripheral blood of RA patients, compared with that in healthy controls. It is known that Tfh cells are critical for directing the development of an antibody response by germinal centers B cells; secondly, we observed that the Tfh-cell frequency is accompanied by the level of anti-CCP antibody in RA patients. Furthermore, expression of Bcl-6 mRNA and plasma IL-21 concentrations in RA patients was increased. Taken together, these findings have shown that the increased frequency of circulating Tfh cells is correlated with elevated levels of anti-CCP antibody, indicating the possible involvement of Tfh cells in the disease progression of RA.

scholarly journals T-bet in Tfh cells: Now you see me, now you don’t

2018 ◽  
Vol 215 (11) ◽  
pp. 2697-2698 ◽  
Author(s):  
Susan M. Kaech
Keyword(s):  
Tfh Cells ◽  
Follicular Helper ◽  
Ifn Γ ◽  
Late Stages

In this issue, Fang et al. (https://doi.org/10.1084/jem.20180927) report on a subset of T follicular helper (Tfh) cells that transiently expresses T-bet yet continues to produce IFN-γ at late stages of GC reactions following immunization. They find other genes uniquely expressed in this IFN-γ–producing Tfh subset, such as NKG2D, that can be used to better distinguish these functionally distinct Tfh cells.

scholarly journals FoxP3 and Ezh2 regulate Tfr cell suppressive function and transcriptional program

2019 ◽  
Vol 216 (3) ◽  
pp. 605-620 ◽  
Author(s):  
Shenda Hou ◽  
Rachel L. Clement ◽  
Alos Diallo ◽  
Bruce R. Blazar ◽  
Alexander Y. Rudensky ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Antibody Production ◽  
Regulatory T Cell ◽  
Cell Subset ◽  
Antibody Responses ◽  
Transcriptional Program ◽  
Suppressive Function ◽  
Tissue Microenvironment ◽  
Follicular Helper

Follicular regulatory T (Tfr) cells are a regulatory T cell subset that controls antibody production by inhibiting T follicular helper (Tfh)–mediated help to B cells. Tfh and Tfr cells possess opposing functions suggesting unique programming. Here we elucidated the transcriptional program controlling Tfr suppressive function. We found that Tfr cells have a program for suppressive function fine-tuned by tissue microenvironment. The transcription factor FoxP3 and chromatin-modifying enzyme EZH2 are essential for this transcriptional program but regulate the program in distinct ways. FoxP3 modifies the Tfh program to induce a Tfr-like functional state, demonstrating that Tfr cells coopt the Tfh program for suppression. Importantly, we identified a Tfr cell population that loses the Tfr program to become “ex-Tfr” cells with altered functionality. These dysfunctional ex-Tfr cells may have roles in modulating pathogenic antibody responses. Taken together, our studies reveal mechanisms controlling the Tfr transcriptional program and how failure of these mechanisms leads to dysfunctional Tfr cells.

scholarly journals Follicular Regulatory T Cells Are Highly Permissive to R5-Tropic HIV-1

2017 ◽  
Vol 91 (17) ◽  
Author(s):  
Shannon M. Miller ◽  
Brodie Miles ◽  
Kejun Guo ◽  
Joy Folkvord ◽  
Amie L. Meditz ◽  
...  
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Cell Subset ◽  
Viral Proteins ◽  
Ki67 Expression ◽  
Lymphoid Follicles ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Hiv 1

ABSTRACT Follicular regulatory T (TFR) cells are a subset of CD4+ T cells in secondary lymphoid follicles. TFR cells were previously included in the follicular helper T (TFH) cell subset, which consists of cells that are highly permissive to HIV-1. The permissivity of TFR cells to HIV-1 is unknown. We find that TFR cells are more permissive than TFH cells to R5-tropic HIV-1 ex vivo. TFR cells expressed more CCR5 and CD4 and supported higher frequencies of viral fusion. Differences in Ki67 expression correlated with HIV-1 replication. Inhibiting cellular proliferation reduced Ki67 expression and HIV-1 replication. Lymph node cells from untreated HIV-infected individuals revealed that TFR cells harbored the highest concentrations of HIV-1 RNA and highest levels of Ki67 expression. These data demonstrate that TFR cells are highly permissive to R5-tropic HIV-1 both ex vivo and in vivo. This is likely related to elevated CCR5 levels combined with a heightened proliferative state and suggests that TFR cells contribute to persistent R5-tropic HIV-1 replication in vivo. IMPORTANCE In chronic, untreated HIV-1 infection, viral replication is concentrated in secondary lymphoid follicles. Within secondary lymphoid follicles, follicular helper T (TFH) cells have previously been shown to be highly permissive to HIV-1. Recently, another subset of T cells in secondary lymphoid follicles was described, follicular regulatory T (TFR) cells. These cells share some phenotypic characteristics with TFH cells, and studies that showed that TFH cells are highly permissive to HIV-1 included TFR cells in their definition of TFH cells. The permissivity of TFR cells to HIV-1 has not previously been described. Here, we show that TFR cells are highly permissive to HIV-1 both ex vivo and in vivo. The expression of Ki67, a marker of proliferative capacity, is predictive of expression of viral proteins, and downregulating Ki67 leads to concurrent decreases in expression of viral proteins. Our study provides new insight into HIV-1 replication and a potential new cell type to target for future treatment.

scholarly journals Critical regulation of follicular helper T cell differentiation and function by Gα13 signaling

2021 ◽  
Vol 118 (43) ◽  
pp. e2108376118
Author(s):  
Da-Sol Kuen ◽  
Miso Park ◽  
Heeju Ryu ◽  
Garam Choi ◽  
Young-Hye Moon ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Vaccine Development ◽  
Cell Subset ◽  
Helper T Cell ◽  
Rock Inhibitor ◽  
Tfh Cells ◽  
Follicular Helper ◽  
And Function ◽  
Deficient Mice

GPCR-Gα protein–mediated signal transduction contributes to spatiotemporal interactions between immune cells to fine-tune and facilitate the process of inflammation and host protection. Beyond this, however, how Gα proteins contribute to the helper T cell subset differentiation and adaptive response have been underappreciated. Here, we found that Gα13 signaling in T cells plays a crucial role in inducing follicular helper T (Tfh) cell differentiation in vivo. T cell–specific Gα13-deficient mice have diminished Tfh cell responses in a cell-intrinsic manner in response to immunization, lymphocytic choriomeningitis virus infection, and allergen challenges. Moreover, Gα13-deficient Tfh cells express reduced levels of Bcl-6 and CXCR5 and are functionally impaired in their ability to adhere to and stimulate B cells. Mechanistically, Gα13-deficient Tfh cells harbor defective Rho-ROCK2 activation, and Rho agonist treatment recuperates Tfh cell differentiation and expression of Bcl-6 and CXCR5 in Tfh cells of T cell–specific Gα13-deficient mice. Conversely, ROCK inhibitor treatment hampers Tfh cell differentiation in wild-type mice. These findings unveil a crucial regulatory role of Gα13-Rho-ROCK axis in optimal Tfh cell differentiation and function, which might be a promising target for pharmacologic intervention in vaccine development as well as antibody-mediated immune disorders.

scholarly journals Abnormalities of follicular helper T-cell number and function in Wiskott-Aldrich syndrome

Blood ◽  
2016 ◽  
Vol 127 (25) ◽  
pp. 3180-3191 ◽  
Author(s):  
Xuan Zhang ◽  
Rongxin Dai ◽  
Wenyan Li ◽  
Hongyi Zhao ◽  
Yongjie Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Subset ◽  
Cell Number ◽  
Wiskott Aldrich Syndrome ◽  
Cell Functions ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Bcl6 Expression

Abstract Wiskott-Aldrich syndrome protein (WASp) is a hematopoietic-specific regulator of actin nucleation. Wiskott-Aldrich syndrome (WAS) patients show immunodeficiencies, most of which have been attributed to defective T-cell functions. T follicular helper (Tfh) cells are the major CD4+ T-cell subset with specialized B-cell helper capabilities. Aberrant Tfh cells activities are involved in immunopathologies such as autoimmunity, immunodeficiencies, and lymphomas. We found that in WAS patients, the number of circulating Tfh cells was significantly reduced due to reduced proliferation and increased apoptosis, and Tfh cells were Th2 and Th17 polarized. The expression of inducible costimulator (ICOS) in circulating Tfh cells was higher in WAS patients than in controls. BCL6 expression was decreased in total CD4+ T and Tfh cells of WAS patients. Mirroring the results in patients, the frequency of Tfh cells in WAS knockout (KO) mice was decreased, as was the frequency of BCL6+ Tfh cells, but the frequency of ICOS+ Tfh cells was increased. Using WAS chimera mice, we found that the number of ICOS+ Tfh cells was decreased in WAS chimera mice, indicating that the increase in ICOS+ Tfh cells in WAS KO mice was cell extrinsic. The data from in vivo CD4+ naive T-cell adoptive transfer mice as well as in vitro coculture of naive B and Tfh cells showed that the defective function of WASp-deficient Tfh cells was T-cell intrinsic. Consistent findings in both WAS patients and WAS KO mice suggested an essential role for WASp in the development and memory response of Tfh cells and that WASp deficiency causes a deficient differentiation defect in Tfh cells by downregulating the transcription level of BCL6.

scholarly journals Broad phenotypic alterations and potential dysfunction of lymphocytes in individuals clinically recovered from COVID-19

2021 ◽  
Author(s):  
Jingyi Yang ◽  
Maohua Zhong ◽  
Ejuan Zhang ◽  
Ke Hong ◽  
Qingyu Yang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Cell Subset ◽  
Effector Memory ◽  
Peripheral Blood Mononuclear ◽  
Follicular Helper ◽  
Hla Dr ◽  
Ifn Γ

Abstract Although millions of patients have clinically recovered from COVID-19, little is known about the immune status of lymphocytes in these individuals. In this study, the peripheral blood mononuclear cells (PBMCs) of a clinically recovered (CR) cohort were comparatively analyzed with those of an age- and sex-matched healthy donor (HD) cohort. We found that CD8+ T cells in the CR cohort had higher numbers of effector T cells and effector memory T cells but lower Tc1 (IFN-γ+), Tc2 (IL-4+), and Tc17 (IL-17A+) cell frequencies. The CD4+ T cells of the CR cohort were decreased in frequency, especially the central memory T cell subset. Moreover, CD4+ T cells in the CR cohort showed lower PD-1 expression and had lower frequencies of Th1 (IFN-γ+), Th2 (IL-4+), Th17 (IL-17A+), and circulating follicular helper T (CXCR5+PD-1+) cells. Accordingly, the proportion of isotype-switched memory B cells (IgM−CD20hi) among B cells in the CR cohort showed a significantly lower proportion, although the level of the activation marker CD71 was elevated. For CD3−HLA-DR− lymphocytes in the CR cohort, in addition to lower levels of IFN-γ, granzyme B, and T-bet, the correlation between T-bet and IFN-γ was not observed. Additionally, by taking into account the number of days after discharge, all the phenotypes associated with reduced function did not show a tendency toward recovery within 4‒11 weeks. The remarkable phenotypic alterations in lymphocytes in the CR cohort suggest that SARS-CoV-2 infection profoundly affects lymphocytes and potentially results in dysfunction even after clinical recovery.

Characterization Of T Follicular Helper Cells In Patients With Low Risk Myelodysplastic Syndromes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4729-4729
Author(s):  
Polyxeni Lampropoulou ◽  
Evgenia Verigou ◽  
Argiris Symeonidis ◽  
Charalambos Gogos ◽  
Elena E. Solomou
Keyword(s):  
Transcription Factor ◽  
Myelodysplastic Syndromes ◽  
T Helper Cells ◽  
Low Risk ◽  
T Helper ◽  
Cd4 Cells ◽  
Tfh Cells ◽  
Control Subjects ◽  
Helper Cells ◽  
Follicular Helper

A subpopulation of CD4+helper T cells, T-follicular helper cells (TFH), are characterized by the surface expression of CXCR5, ICOS, and PD1, the transcription factor Bcl-6, and produce mainly IL-21, but also IL-17, IL-4, and IFN-γ. They represent the major population that helps B cells to turn into plasma cells and they are implicated in the pathogenesis of different autoimmune diseases. Peripheral CXCR5+CD4+ T helper cells (p-TFH) are the circulating component of TFH. p-TFH cells have been extensively studied in the context of inflammation and autoimmunity. Patients with systemic lupus erythematosus and rheumatoid arthritis have increased p-TFH. Immune dysregulation characterizes low risk myelodysplastic syndromes (MDS). The expression of p-TFH in patients in low risk MDS has not been previously evaluated. To examine the expression of p-TFH in this disease we isolated peripheral blood mononuclear cells (PBMCs) from patients with low risk MDS (n=20, Refractory Anemia,RA; and Refractory Cytopenias with Multilineage Dysplasia, RCMD) and ten healthy, age- matched controls. Written informed consent was obtained from all study subjects. PBMCs were left untreated or activated with PMA and Ionomycin, in the presence of Brefeldin A, for 5 hours. Subsequently, cells were stained with the surface markers CXCR5, CD4, CD45RO, ICOS and intracellular IL-21, and analyzed by flow cytometry. Patients with MDS show decreased CD4+ICOS+ cells compared to healthy controls (5,34±1,44% vs 8,69±4,08% respectively, p=0.028). The median percentages of CXCR5+CD4+ cells (estimated on CD4+ cells) before stimulation were lower in MDS patients although not statistically significant different from the control subjects. The expansion of the CXCR5+CD4+ population after stimulation was higher in MDS patients compared to healthy individuals (ratio of stimulated to unstimulated CXCR5+CD4+ cells of MDS patients: 1.44±0.47 vs control: 1.23± 0.32, p=0.027). MDS patients at diagnosis showed increased median levels of IL-21 producing CXCR5+CD4+ cells compared to patients previously treated with erythropoietin (EPO), (21,34±10,14% vs 17,55±12,91, respectively). Additionally, patients with RA showed increased CXCR5+CD4+IL-21+ cells compared to the RCMD patients (22,39±11,76% vs 17,84±10,70%, respectively). Collectively, the percentage of IL-21 producing CXCR5+CD4+ cells did not differ significantly between the MDS and control groups (20,57± 10,12% vs 19,86± 11,03%, respectively). The presence of marrow fibrosis did not affect the differences observed and described above. The p-TFH cell subset was identified in every case as a memory component of CD4+ T helper cells, as previously described. Although the number of patients analyzed is limited, our results suggest that low risk MDS patients show a trend of lower CXCR5+CD4+ cells compared to age–matched control subjects. EPO treatment eliminates IL-21 production from CXCR5+CD4+ cells compared to treatment-naïve patients. Further analysis of a larger pool of subjects along with the examination of the specific transcription factor Bcl-6 will reveal the role of p-TFH cells in low risk MDS. Disclosures: No relevant conflicts of interest to declare.

Effects of Follicular Helper T Cells and Inflammatory Cytokines on Myasthenia Gravis

2019 ◽  
Vol 19 (10) ◽  
pp. 739-745
Author(s):  
Lifang Wang ◽  
Yu Zhang ◽  
Mingqin Zhu ◽  
Jiachun Feng ◽  
Jinming Han ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Inflammatory Cytokines ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Gradient Centrifugation ◽  
Peripheral Blood Mononuclear ◽  
Th Cells ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Ifn Γ

Background: Myasthenia gravis (MG) is an autoimmune disorder mediated by antibodies against the acetylcholine receptors (AChR) of the skeletal muscles. An imbalance in various T helper (Th) cells, including Th1, Th2, Th17, Th22 and follicular helper T (TFH) cells, has been found associated with immunological disturbances. Objective: In this study, we aim to investigate the role of the Th cells in peripheral blood of MG patients. Materials and Methods: A total of 33 MG patients and 34 age matched controls were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll-Paque density gradient centrifugation assay. The proportion of TFH cells in PBMC were analyzed using flow-cytometry assay by determining the levels of cellular markers CD4, CXCR5, CD45RO, CD45RA and ICOS and PD-1. The levels of IFN-γ, IL-4, IL-17 and IL-21 in serum were analyzed by Cytometric Bead Array. The serum IL-22 level was analyzed by ELISA. Results: The frequency of TFH cells in PBMCs was higher than those in healthy subjects and correlated to the severity of MG patients. The levels of pro-inflammatory cytokines IFN-γ, IL-17 and IL-21 were elevated in the serum of MG patients, while there were no significant differences regarding the levels of IL-4 and IL-22 between MG patients and control subjects. Conclusion: Our findings suggest that Th cells and their cytokines balance of MG patients are involved in the clinical condition or severity of MG disease.

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