scholarly journals Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Long-Shan Ji ◽  
Xue-Hua Sun ◽  
Xin Zhang ◽  
Zhen-Hua Zhou ◽  
Zhuo Yu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Differentiation ◽  
B Cells ◽  
T Helper Cells ◽  
Molecular Mechanisms ◽  
Transcriptional Level ◽  
T Helper ◽  
Tfh Cells ◽  
Helper Cells ◽  
Follicular Helper

Helping B cells and antibody responses is a major function of CD4+T helper cells. Follicular helper T (Tfh) cells are identified as a subset of CD4+T helper cells, which is specialized in helping B cells in the germinal center reaction. Tfh cells express high levels of CXCR5, PD-1, IL-21, and other characteristic markers. Accumulating evidence has demonstrated that the dysregulation of Tfh cells is involved in infectious, inflammatory, and autoimmune diseases, including lymphocytic choriomeningitis virus (LCMV) infection, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), IgG4-related disease (IgG4-RD), Sjögren syndrome (SS), and type 1 diabetes (T1D). Activation of subset-specific transcription factors is the essential step for Tfh cell differentiation. The differentiation of Tfh cells is regulated by a complicated network of transcription factors, including positive factors (Bcl6, ATF-3, Batf, IRF4, c-Maf, and so on) and negative factors (Blimp-1, STAT5, IRF8, Bach2, and so on). The current knowledge underlying the molecular mechanisms of Tfh cell differentiation at the transcriptional level is summarized in this paper, which will provide many perspectives to explore the pathogenesis and treatment of the relevant immune diseases.

scholarly journals Dual regulation of IRF4 function in T and B cells is required for the coordination of T–B cell interactions and the prevention of autoimmunity

2012 ◽  
Vol 209 (3) ◽  
pp. 581-596 ◽  
Author(s):  
Partha S. Biswas ◽  
Sanjay Gupta ◽  
Roslynn A. Stirzaker ◽  
Varsha Kumar ◽  
Rolf Jessberger ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
T Helper Cells ◽  
Regulatory Protein ◽  
Cell Interactions ◽  
T Helper ◽  
T And B Cells ◽  
Helper Cells

Effective humoral responses to protein antigens require the precise execution of carefully timed differentiation programs in both T and B cell compartments. Disturbances in this process underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE). Interferon regulatory factor 4 (IRF4) is induced upon the activation of T and B cells and serves critical functions. In CD4+ T helper cells, IRF4 plays an essential role in the regulation of IL-21 production, whereas in B cells it controls class switch recombination and plasma cell differentiation. IRF4 function in T helper cells can be modulated by its interaction with regulatory protein DEF6, a molecule that shares a high degree of homology with only one other protein, SWAP-70. Here, we demonstrate that on a C57BL/6 background the absence of both DEF6 and SWAP-70 leads to the development of a lupus-like disease in female mice, marked by simultaneous deregulation of CD4+ T cell IL-21 production and increased IL-21 B cell responsiveness. We furthermore show that DEF6 and SWAP-70 are differentially used at distinct stages of B cell differentiation to selectively control the ability of IRF4 to regulate IL-21 responsiveness in a stage-specific manner. Collectively, these data provide novel insights into the mechanisms that normally couple and coordinately regulate T and B cell responses to ensure tight control of productive T–B cell interactions.

Molecular mechanisms for B lymphocyte selection: induction and regulation of antigen-receptor-mediated apoptosis of mature B cells in normal mice and their defect in autoimmunity-prone mice

1994 ◽  
Vol 345 (1313) ◽  
pp. 297-301 ◽  
Keyword(s):  
Immune System ◽  
B Cells ◽  
B Cell ◽  
T Helper Cells ◽  
Molecular Mechanisms ◽  
B Lymphocyte ◽  
Antigen Receptor ◽  
Normal Function ◽  
T Helper ◽  
Helper Cells

Apoptosis (programmed cell death) has been suggested to be involved in clonal elimination of selfreactive lymphocytes for the normal function of the immune system. By crosslinking the antigen receptor (surface immunoglobulin; slg) on the peritoneal B cells of normal mice, we found that strong crosslinking of slg induces apoptosis of mature B cells, suggesting that interaction with membranebound self-antigens may eliminate self-reactive mature B cells by apoptosis. Antigen-receptor-mediated B cell apoptosis is blocked when a signal is transduced via the CD40 molecule on the B cell surface. Because the ligand of CD40 (CD40L) is expressed on activated T helper cells, B cells may escape from apoptosis and are activated when the immune system interacts with foreign antigens, which are normally able to activate T helper cells. Moreover, slg crosslinking fails to induce apoptosis of both bcl-2-transgenic mice and autoimmune-disease-prone New Zealand mice. In these mice, the defect in slg-mediated apoptosis of mature B cells may allow generation of self-reactive B cells, resulting in pathogenic consequences.

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.

scholarly journals Activated human CD25+B cells are able to induce cell cycle arrest and apoptosis in CD4+T‐Helper cells

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Theresa Tretter ◽  
Ram Kumar Venigalla ◽  
Volker Eckstein ◽  
Rainer Saffrich ◽  
Lorenz Hanns‐Martin
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
Cell Cycle Arrest ◽  
T Helper Cells ◽  
T Helper ◽  
Induce Cell Cycle Arrest ◽  
Helper Cells ◽  
Cycle Arrest

scholarly journals An idiotype-specific helper population that bears immunoglobulin, Ia, and Lyt-1 determinants.

1984 ◽  
Vol 159 (4) ◽  
pp. 1189-1200 ◽  
Author(s):  
D H Sherr ◽  
M E Dorf
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cell Population ◽  
T Helper Cells ◽  
T Helper ◽  
Phenotypic Characteristics ◽  
Surface Phenotype ◽  
Specific Recognition ◽  
Helper Cells ◽  
Helper Activity

A helper cell population with phenotypic characteristics of both B and T cells is described. This helper population, called BH, is present in normal unprimed C57BL/6 mice and preferentially helps the expression of NPb idiotype-bearing plaque-forming B cells in the absence of T helper cells. Its surface phenotype is Lyt-1.2+, Ig+, Lyb-3+, Thy-1.2-, Lyt-2.2-. The helper activity of the BH population is IgH restricted and BH cells selectively bind NPb idiotypic determinants. Collectively the data demonstrate that this unique subpopulation can regulate the response of antibody-secreting B cells through specific recognition of idiotypic determinants.

scholarly journals Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

2020 ◽  
Author(s):  
Amania A. Sheikh ◽  
Joanna R. Groom
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Inflammatory Responses ◽  
Immune Memory ◽  
Transcriptional Networks ◽  
T Helper ◽  
T Helper 1 ◽  
Extrinsic Factors ◽  
Tfh Cells ◽  
Follicular Helper

Abstract During viral infection, immune cells coordinate the induction of inflammatory responses that clear infection and humoral responses that promote protection. CD4+ T-cell differentiation sits at the center of this axis. Differentiation toward T-helper 1 (Th1) cells mediates inflammation and pathogen clearance, while T follicular helper (Tfh) cells facilitate germinal center (GC) reactions for the generation of high-affinity antibodies and immune memory. While Th1 and Tfh differentiation occurs in parallel, these CD4+ T-cell identities are mutually exclusive, and progression toward these ends is determined via the upregulation of T-bet and Bcl6, respectively. These lineage-defining transcription factors act in concert with multiple networks of transcriptional regulators that tip the T-bet and Bcl6 axis in CD4+ T-cell progenitors to either a Th1 or Tfh fate. It is now clear that these transcriptional networks are guided by cytokine cues that are not only varied between distinct viral infections but also dynamically altered throughout the duration of infection. Thus, multiple intrinsic and extrinsic factors combine to specify the fate, plasticity, and function of Th1 and Tfh cells during infection. Here, we review the current information on the mode of action of the lineage-defining transcription factors Bcl6 and T-bet and how they act individually and in complex to govern CD4+ T-cell ontogeny. Furthermore, we outline the multifaceted transcriptional regulatory networks that act upstream and downstream of Bcl6 and T-bet to tip the differentiation equilibrium toward either a Tfh or Th1 fate and how these are impacted by dynamic inflammatory cues.

scholarly journals A distinct subpopulation of CD25− T-follicular regulatory cells localizes in the germinal centers

2017 ◽  
Vol 114 (31) ◽  
pp. E6400-E6409 ◽  
Author(s):  
James Badger Wing ◽  
Yohko Kitagawa ◽  
Michela Locci ◽  
Hannah Hume ◽  
Christopher Tay ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Germinal Center ◽  
Germinal Centers ◽  
Regulatory Cells ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Distinct Subpopulation ◽  
Wide Range ◽  
Multistep Process

T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differentiation is inhibited by IL-2, regulatory T (Treg) cell differentiation and survival depend on it. Here, we describe a CD25− subpopulation within both murine and human PD1+CXCR5+Foxp3+ Tfr cells. It is preferentially located in the GC and can be clearly differentiated from CD25+ non–GC-Tfr, Tfh, and effector Treg (eTreg) cells by the expression of a wide range of molecules. In comparison to CD25+ Tfr and eTreg cells, CD25− Tfr cells partially down-regulate IL-2–dependent canonical Treg features, but retain suppressive function, while simultaneously up-regulating genes associated with Tfh and GC-Tfh cells. We suggest that, similar to Tfh cells, Tfr cells follow a differentiation pathway generating a mature GC-localized subpopulation, CD25− Tfr cells.

scholarly journals Mucosal T follicular helper cells in SIV-infected rhesus macaques: contributing role of IL-27

2019 ◽  
Vol 12 (4) ◽  
pp. 1038-1054 ◽  
Author(s):  
Félicien Moukambi ◽  
Henintsoa Rabezanahary ◽  
Yasmina Fortier ◽  
Vasco Rodrigues ◽  
Julien Clain ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd4 T Cells ◽  
Rhesus Macaques ◽  
T Follicular Helper Cells ◽  
Mesenteric Lymph Nodes ◽  
Tfh Cells ◽  
Helper Cells ◽  
Follicular Helper ◽  
Memory Cd4 T Cells

AbstractMesenteric lymph nodes (MLNs), that drain the large and small intestine, are critical sites for the induction of oral tolerance. Although depletion of CD4 T cells in the intestinal lamina propria is a hallmark of HIV infection, CD4 T cell dynamics in MLNs is less known due to the lack of accessibility to these LNs. We demonstrate the early loss of memory CD4 T cells, including T follicular helper cells (Tfh) and a remodeling of MLN architecture in SIV-infected rhesus macaques (RMs). Along with the loss of Tfh cells, we observe the loss of memory B cells and of germinal center B cells. Tfh cells display a Th1 profile with increased levels of the transcription factors that negatively impact on Tfh differentiation and of Stat5 phosphorylation. MLNs of SIV-infected RMs display lower mRNA transcripts encoding for IL-12, IL-23, and IL-35, whereas those coding for IL-27 are not impaired in MLNs. In vitro, IL-27 negatively impacts on Tfh cells and recapitulates the profile observed in SIV-infected RMs. Therefore, early defects of memory CD4 T cells, as well of Tfh cells in MLNs, which play a central role in regulating the mucosal immune response, may have major implications for Aids.

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