scholarly journals Neuropilin-1 Expression Characterizes T Follicular Helper (Tfh) Cells Activated during B Cell Differentiation in Human Secondary Lymphoid Organs

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e85589 ◽  
Author(s):  
Amédée Renand ◽  
Pierre Milpied ◽  
Julien Rossignol ◽  
Julie Bruneau ◽  
François Lemonnier ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Lymphoid Organs ◽  
B Cell Differentiation ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Neuropilin 1 ◽  
Secondary Lymphoid Organs

Imbalance toward TFH 1 cells playing a role in aberrant B cell differentiation in systemic sclerosis

Rheumatology ◽  
2020 ◽  
Author(s):  
Nhung Thi My Ly ◽  
Ikuko Ueda-Hayakawa ◽  
Chuyen Thi Hong Nguyen ◽  
Trang Nguyen Mai Huynh ◽  
Izumi Kishimoto ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Skin Lesions ◽  
B Cell Differentiation ◽  
Multisystem Disorder ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Cytokine Levels ◽  
Th17 Cytokines ◽  
High Level

Abstract Objective SSc is a connective tissue disease with multisystem disorder induced by the inflammation and fibrosis following T and B cell abnormalities. Follicular helper CD4+ T (TFH) cells play a crucial role in the formation of germinal centres and specialize in interacting to aid B cell differentiation. We aimed to investigate TFH cells and their subsets to evaluate their involvement with B cell alteration in SSc. Method Circulating TFH cells (cTFH), B cells and their subsets were assessed by flow cytometry. The concentration of serum cytokines was measured by cytokine array assay. Immunohistochemistry and IF were performed to evaluate the migration of TFH cells in SSc skin lesions. Results The proportion of cTFH cells did not differ from controls, but their subsets were imbalanced in SSc patients. The frequency of TFH 1 was increased and correlated with ACA titre, serum IgM or CRP levels of patients, and cytokine concentrations of IL-21 and IL-6 that induce B cell differentiation in SSc. cTFH cells from SSc showed activated phenotype with expressing higher cytokine levels compared with controls. The frequency of TFH 17 was also increased, but was not correlated with a high level of Th17 cytokines in patients’ sera. Furthermore, infiltration of TFH cells was found in skin lesion of SSc patients. Conclusion We here describe an imbalance of cTFH toward TFH 1 that may induce B cell alteration through IL-21 and IL-6 pathways and promote inflammation, contributing to the pathogenesis of SSc disease.

scholarly journals Regulation of Intrinsic and Bystander T Follicular Helper Cell Differentiation and Autoimmunity by Tsc1

2021 ◽  
Vol 12 ◽  
Author(s):  
Shimeng Zhang ◽  
Lei Li ◽  
Danli Xie ◽  
Srija Reddy ◽  
John W. Sleasman ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Immune Responses ◽  
B Cell ◽  
Regulatory Cells ◽  
Wild Type ◽  
Autoantibody Production ◽  
Cell Responses ◽  
Tfh Cells ◽  
Follicular Helper

T Follicular helper (Tfh) cells promote germinal center (GC) B cell responses to develop effective humoral immunity against pathogens. However, dysregulated Tfh cells can also trigger autoantibody production and the development of autoimmune diseases. We report here that Tsc1, a regulator for mTOR signaling, plays differential roles in Tfh cell/GC B cell responses in the steady state and in immune responses to antigen immunization. In the steady state, Tsc1 in T cells intrinsically suppresses spontaneous GC-Tfh cell differentiation and subsequent GC-B cell formation and autoantibody production. In immune responses to antigen immunization, Tsc1 in T cells is required for efficient GC-Tfh cell expansion, GC-B cell induction, and antigen-specific antibody responses, at least in part via promoting GC-Tfh cell mitochondrial integrity and survival. Interestingly, in mixed bone marrow chimeric mice reconstituted with both wild-type and T cell-specific Tsc1-deficient bone marrow cells, Tsc1 deficiency leads to enhanced GC-Tfh cell differentiation of wild-type CD4 T cells and increased accumulation of wild-type T regulatory cells and T follicular regulatory cells. Such bystander GC-Tfh cell differentiation suggests a potential mechanism that could trigger self-reactive GC-Tfh cell/GC responses and autoimmunity via neighboring GC-Tfh cells.

scholarly journals Extracellular matrix protein 1 promotes follicular helper T cell differentiation and antibody production

2018 ◽  
Vol 115 (34) ◽  
pp. 8621-8626 ◽  
Author(s):  
Lan He ◽  
Wangpeng Gu ◽  
Meng Wang ◽  
Xiaoyan Chang ◽  
Xiaoyu Sun ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Differentiation ◽  
B Cell ◽  
Antibody Production ◽  
Germinal Center ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
B Cell Differentiation ◽  
Follicular Helper ◽  
Extracellular Matrix Protein 1

T-follicular helper (TFH) cells are a subset of CD4+ helper T cells that help germinal center (GC) B-cell differentiation and high-affinity antibody production during germinal center reactions. Whether important extracellular molecules control TFH differentiation is not fully understood. Here, we demonstrate that a secreted protein extracellular matrix protein 1 (ECM1) is critical for TFH differentiation and antibody response. A lack of ECM1 inhibited TFH cell development and impaired GC B-cell reactions and antigen-specific antibody production in an antigen-immunized mouse model. ECM1 was induced by IL-6 and IL-21 in TFH cells, promoting TFH differentiation by down-regulating the level of STAT5 phosphorylation and up-regulating Bcl6 expression. Furthermore, injection of recombinant ECM1 protein into mice infected with PR8 influenza virus promoted protective immune responses effectively, by enhancing TFH differentiation and neutralizing antibody production. Collectively, our data identify ECM1 as a soluble protein to promote TFH cell differentiation and antibody production.

scholarly journals B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells

2011 ◽  
Vol 208 (7) ◽  
pp. 1377-1388 ◽  
Author(s):  
Sau K. Lee ◽  
Robert J. Rigby ◽  
Dimitra Zotos ◽  
Louis M. Tsai ◽  
Shimpei Kawamoto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Antibody Responses ◽  
B Cell Differentiation ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Microbial Infections

T follicular helper cells (Tfh cells) localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell–expressed Bcl-6 significantly reduces T-dependent extrafollicular antibody responses. Bcl-6+ T cells appear at the T–B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6+ PD-1hi T cells, which are found within the GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl-6+ T cells are necessary at B cell priming to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells.

scholarly journals IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism

2010 ◽  
Vol 207 (2) ◽  
pp. 365-378 ◽  
Author(s):  
Dimitra Zotos ◽  
Jonathan M. Coquet ◽  
Yang Zhang ◽  
Amanda Light ◽  
Kathy D'Costa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Target Cells ◽  
B Cell Differentiation ◽  
Follicular Helper

Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.

scholarly journals Differentiation, functions, and roles of T follicular regulatory cells in autoimmune diseases

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
He Hao ◽  
Shingo Nakayamada ◽  
Yoshiya Tanaka
Keyword(s):  
Cell Differentiation ◽  
Autoimmune Diseases ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Regulatory Cells ◽  
Autoantibody Production ◽  
Follicular Helper ◽  
Autoantibody Response

AbstractT follicular helper cells participate in stimulating germinal center (GC) formation and supporting B cell differentiation and autoantibody production. However, T follicular regulatory (Tfr) cells suppress B cell activation. Since changes in the number and functions of Tfr cells lead to dysregulated GC reaction and autoantibody response, targeting Tfr cells may benefit the treatment of autoimmune diseases. Differentiation of Tfr cells is a multistage and multifactorial process with various positive and negative regulators. Therefore, understanding the signals regulating Tfr cell generation is crucial for the development of targeted therapies. In this review, we discuss recent studies that have elucidated the roles of Tfr cells in autoimmune diseases and investigated the modulators of Tfr cell differentiation. Additionally, potential immunotherapies targeting Tfr cells are highlighted.

scholarly journals Crosstalk Between Circulating Follicular T Helper Cells and Regulatory B Cells in Children With Extrinsic Atopic Dermatitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinqiu Jiang ◽  
Shi Yan ◽  
Xiaoying Zhou ◽  
Jinghua Zhou ◽  
Xiaoming Bai ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Cell Differentiation ◽  
B Cell ◽  
Critical Role ◽  
Allergic Inflammation ◽  
Cell Receptor ◽  
Dependent Manner ◽  
B Cell Differentiation ◽  
Initial Manifestation ◽  
Tfh Cells

Atopic dermatitis (AD) in early childhood is often the initial manifestation of allergic disease associated with high IgE. Accumulating evidences show that follicular helper T (Tfh) cells play a critical role in promoting B cell differentiation and IgE production, human regulatory B (Breg) cells participate in immunomodulatory processes and inhibition of allergic inflammation. However, the roles and interactions between IL-10-producing Breg cells and Tfh cells in childhood AD are unclear. In this study, we found that the percentage of CD19+IL-10+ Breg cells in children with extrinsic AD was significantly lower than that in age-matched healthy controls, and that it correlated negatively with enhanced CD4+CXCR5+PD-1+ICOS+ circulating Tfh cell responses and increased disease activity; however, there was no significant correlation with serum total IgE levels. A co-culture system revealed that Breg cells from patients with extrinsic AD cannot effectively inhibit differentiation of Tfh cells in an IL-10 dependent manner. Abnormal pSTAT3 signaling induced via Toll-like receptors (TLR), but not the B-cell receptor (BCR) signaling, might contribute to the defect of Breg cells in AD. Taken together, these observations demonstrate an important role for IL-10-producing Breg cells in inhibiting Tfh cell differentiation, and suggest that they may participate in the pathogenesis of AD.

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