scholarly journals Germinal Center T follicular helper (GC-Tfh) cell impairment in chronic HIV infection involves c-Maf signaling

2021 ◽  
Vol 17 (7) ◽  
pp. e1009732
Author(s):  
Marita Chakhtoura ◽  
Mike Fang ◽  
Rafael Cubas ◽  
Margaret H. O’Connor ◽  
Carmen N. Nichols ◽  
...  
Keyword(s):  
B Cells ◽  
Hiv Infection ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Cell Functions ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Factor C ◽  
Anti Hiv

We have recently demonstrated that the function of T follicular helper (Tfh) cells from lymph nodes (LN) of HIV-infected individuals is impaired. We found that these cells were unable to provide proper help to germinal center (GC)-B cells, as observed by altered and inefficient anti-HIV antibody response and premature death of memory B cells. The underlying molecular mechanisms of this dysfunction remain poorly defined. Herein, we have used a unique transcriptional approach to identify these molecular defects. We consequently determined the transcriptional profiles of LN GC-Tfh cells following their interactions with LN GC-B cells from HIV-infected and HIV-uninfected individuals, rather than analyzing resting ex-vivo GC-Tfh cells. We observed that proliferating GC-Tfh cells from HIV-infected subjects were transcriptionally different than their HIV-uninfected counterparts, and displayed a significant downregulation of immune- and GC-Tfh-associated pathways and genes. Our results strongly demonstrated that MAF (coding for the transcription factor c-Maf) and its upstream signaling pathway mediators (IL6R and STAT3) were significantly downregulated in HIV-infected subjects, which could contribute to the impaired GC-Tfh and GC-B cell functions reported during infection. We further showed that c-Maf function was associated with the adenosine pathway and that the signaling upstream c-Maf could be partially restored by adenosine deaminase -1 (ADA-1) supplementation. Overall, we identified a novel mechanism that contributes to GC-Tfh cell impairment during HIV infection. Understanding how GC-Tfh cell function is altered in HIV is crucial and could provide critical information about the mechanisms leading to the development and maintenance of effective anti-HIV antibodies.

scholarly journals Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine

Blood ◽  
2012 ◽  
Vol 120 (5) ◽  
pp. 985-993 ◽  
Author(s):  
Suresh Pallikkuth ◽  
Anita Parmigiani ◽  
Sandra Y. Silva ◽  
Varghese K. George ◽  
Margaret Fischl ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Function ◽  
Cell Loss ◽  
H1n1 Influenza ◽  
Pbmc Culture ◽  
Tfh Cells ◽  
Follicular Helper ◽  
2009 H1n1

Abstract The generation of Ab-secreting plasma cells depends critically on CD4 T-follicular helper (TFH) cells during the germinal center reaction. Germinal center TFH cells share functional properties with circulating CXCR5+ CD4 T cells, referred to herein as peripheral TFH (pTFH) cells. Because deficient Ab production and CD4 T-cell loss are recognized features of HIV infection, in the present study, we investigated pTFH cells in 25 HIV-infected patients on antiretroviral therapy. pTFH frequency was equivalent in patients and healthy controls (HCs), and these cells displayed a central memory phenotype. Sixteen patients and 8 HCs in this group were given a single dose of H1N1/09 influenza vaccine during the 2009 H1N1 influenza outbreak. In the vaccine responders (n = 8) and HCs, pTFH cells underwent expansion with increased IL-21 and CXCL13 secretion in H1N1-stimulated PBMC culture supernatants at week 4 (T2). These changes were not seen in vaccine nonresponders (n = 8). In coculture experiments, sorted pTFH cells supported HIN1-stimulated IgG production by autologous B cells only in vaccine responders. At T2, frequencies of pTFH were correlated with memory B cells, serum H1N1 Ab titers, and Ag-induced IL-21 secretion. Characterization of pTFH cells may provide additional insight into cellular determinants of vaccine-induced Ab response, which may have relevance for vaccine design.

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 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 Germinal Center Cells Turning to the Dark Side: Neoplasms of B Cells, Follicular Helper T Cells, and Follicular Dendritic Cells

2021 ◽  
Vol 10 ◽  
Author(s):  
Rosario Munguía-Fuentes ◽  
Raúl Antonio Maqueda-Alfaro ◽  
Rommel Chacón-Salinas ◽  
Leopoldo Flores-Romo ◽  
Juan Carlos Yam-Puc
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
Germinal Center ◽  
Great Part ◽  
Metastatic Potential ◽  
Dark Side ◽  
Follicular Dendritic Cells ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Follicular Dendritic

Gaining knowledge of the neoplastic side of the three main cells—B cells, Follicular Helper T (Tfh) cells, and follicular dendritic cells (FDCs) —involved in the germinal center (GC) reaction can shed light toward further understanding the microuniverse that is the GC, opening the possibility of better treatments. This paper gives a review of the more complex underlying mechanisms involved in the malignant transformations that take place in the GC. Whilst our understanding of the biology of the GC-related B cell lymphomas has increased—this is not reviewed in detail here—the dark side involving neoplasms of Tfh cells and FDCs are poorly studied, in great part, due to their low incidence. The aggressive behavior of Tfh lymphomas and the metastatic potential of FDCs sarcomas make them clinically relevant, merit further attention and are the main focus of this review. Tfh cells and FDCs malignancies can often be misdiagnosed. The better understanding of these entities linked to their molecular and genetic characterization will lead to prediction of high-risk patients, better diagnosis, prognosis, and treatments based on molecular profiles.

scholarly journals NR4A1 Deletion in Marginal Zone B Cells Exacerbates Atherosclerosis in Mice—Brief Report

2020 ◽  
Vol 40 (11) ◽  
pp. 2598-2604
Author(s):  
Meritxell Nus ◽  
Gemma Basatemur ◽  
Maria Galan ◽  
Laia Cros-Brunsó ◽  
Tian X. Zhao ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Marginal Zone ◽  
Cell Function ◽  
Cell Receptor ◽  
Marginal Zone B Cells ◽  
Follicular Helper ◽  
Center Axis ◽  
Cell Deletion

Objective: NR4A orphan receptors have been well studied in vascular and myeloid cells where they play important roles in the regulation of inflammation in atherosclerosis. NR4A1 (nerve growth factor IB) is among the most highly induced transcription factors in B cells following BCR (B-cell receptor) stimulation. Given that B cells substantially contribute to the development of atherosclerosis, we examined whether NR4A1 regulates B-cell function during atherogenesis. Approach and Results: We found that feeding Ldlr −/− mice a Western diet substantially increased Nr4a1 expression in marginal zone B (MZB) cells compared with follicular B cells. We then generated Ldlr −/− mice with complete B- or specific MZB-cell deletion of Nr4a1 . Complete B-cell deletion of Nr4a1 led to increased atherosclerosis, which was accompanied by increased T follicular helper cell–germinal center axis response, as well as increased serum total cholesterol and triglycerides levels. Interestingly, specific MZB-cell deletion of Nr4a1 increased atherosclerosis in association with an increased T follicular helper–germinal center response but without any impact on serum cholesterol or triglyceride levels. Nr4a1 −/− MZB cells showed decreased PDL1 (programmed death ligand-1) expression, which may have contributed to the enhanced T follicular helper response. Conclusions: Our findings reveal a previously unsuspected role for NR4A1 in the atheroprotective role of MZB cells.

scholarly journals Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers

2014 ◽  
Vol 211 (7) ◽  
pp. 1297-1305 ◽  
Author(s):  
Saya Moriyama ◽  
Noriko Takahashi ◽  
Jesse A. Green ◽  
Shohei Hori ◽  
Masato Kubo ◽  
...  
Keyword(s):  
T Cells ◽  
Germinal Center ◽  
Molecular Mechanisms ◽  
Germinal Centers ◽  
Antibody Responses ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Sphingosine 1 Phosphate ◽  
Follicular Helper T Cell ◽  
Cell Follicle

Follicular helper T (Tfh) cells access the B cell follicle to promote antibody responses and are particularly important for germinal center (GC) reactions. However, the molecular mechanisms of how Tfh cells are physically associated with GCs are incompletely understood. We report that the sphingosine-1-phosphate receptor 2 (S1PR2) gene is highly expressed in a subpopulation of Tfh cells that localizes in GCs. S1PR2-deficient Tfh cells exhibited reduced accumulation in GCs due to their impaired retention. T cells deficient in both S1PR2 and CXCR5 were ineffective in supporting GC responses compared with T cells deficient only in CXCR5. These results suggest that S1PR2 and CXCR5 cooperatively regulate localization of Tfh cells in GCs to support GC responses.

scholarly journals Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells

2017 ◽  
Vol 214 (5) ◽  
pp. 1259-1267 ◽  
Author(s):  
Nike J. Kräutler ◽  
Dan Suan ◽  
Danyal Butt ◽  
Katherine Bourne ◽  
Jana R. Hermes ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Protective Immunity ◽  
Plasma Cells ◽  
Discrete Subset ◽  
Autoantibody Production ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper

Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, the process whereby GC B cells differentiate into PCs is uncharacterized, and the mechanism underlying the selective PC differentiation of only high-affinity GC B cells remains unknown. In this study, we show that differentiation into PCs is induced among a discrete subset of high-affinity B cells residing within the light zone of the GC. Initiation of differentiation required signals delivered upon engagement with intact antigen. Signals delivered by T follicular helper cells were not required to initiate differentiation but were essential to complete the differentiation process and drive migration of maturing PCs through the dark zone and out of the GC. This bipartite or two-signal mechanism has likely evolved to both sustain protective immunity and avoid autoantibody production.

scholarly journals CTLA-4 expression by B-1a B cells is essential for immune tolerance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yang Yang ◽  
Xiao Li ◽  
Zhihai Ma ◽  
Chunlin Wang ◽  
Qunying Yang ◽  
...  
Keyword(s):  
B Cells ◽  
Transcriptional Activation ◽  
Cell Function ◽  
Critical Function ◽  
Cell Dysfunction ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Autoimmune Pathology ◽  
Important Regulator ◽  
Antigen Presenting

AbstractCTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life. This impaired immune homeostasis results from B-1a cell dysfunction upon loss of CTLA-4. Therefore, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism.

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

2021 ◽  
Vol 118 (18) ◽  
pp. e2016855118
Author(s):  
Kartika Padhan ◽  
Eirini Moysi ◽  
Alessandra Noto ◽  
Alexander Chassiakos ◽  
Khader Ghneim ◽  
...  
Keyword(s):  
B Cells ◽  
Synapse Formation ◽  
Cell Function ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Molecular Determinants ◽  
Spatial Positioning ◽  
To Receive

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.

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