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.

scholarly journals Human follicular CD4 T cell function is defined by specific molecular, positional and TCR dynamic signatures

2020 ◽  
Author(s):  
Kartika Padhan ◽  
Eirini Moysi ◽  
Alessandra Noto ◽  
Alexander Chassiakos ◽  
Khader Ghneim ◽  
...  
Keyword(s):  
T Cell ◽  
Synapse Formation ◽  
Cell Function ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Tissue Organization ◽  
Spatial Positioning ◽  
And Function

AbstractThe orchestrated interaction between follicular helper CD4 T cells (TFH) and germinal center (GC) B cells is crucial for optimal humoral immunity. However, the regulatory mechanisms behind spatial distribution and function of TFH is not well understood. Here, we studied human TFH cells and found that transitioning to a CD57hi TFH status was associated with distinct positioning in the GC, phenotype, transcriptional signatures, function and downregulation of their T-cell receptor (TCR). Single cell TCR clonotype analysis indicated a unidirectional transition towards the CD57hi TFH status, which was marked with drastic changes in the nature of immunological synapse formation where peripheral microclusters become dominant. Lack of central supra molecular activation cluster (cSMAC) formation in TFH synapse was associated with enhanced ubiquitination/proteasome activity in these cells. Our data reveal significant aspects of the tissue organization and heterogeneity of follicular adaptive immunity and suggest that CD57hi TFH cells are endowed with distinctive programming and spatial positioning for optimal GC B cell help.One Sentence Summaryhuman TFH cell heterogeneity

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 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 Atypical B cells upregulate co-stimulatory molecules during malaria and secrete antibodies with T follicular helper cell support

2021 ◽  
Author(s):  
Christine S. Hopp ◽  
Jeff Skinner ◽  
Sarah L. Anzick ◽  
Christopher M. Tipton ◽  
Mary E. Peterson ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Somatic Hypermutation ◽  
Acute Infection ◽  
Cell Receptor ◽  
Tfh Cells ◽  
Influenza Hemagglutinin ◽  
Follicular Helper ◽  
T Cell Help

ABSTRACTSeveral infectious and autoimmune diseases are associated with an expansion of CD21-CD27- atypical B cells (atBCs). The function of atBCs remains unclear and few studies have investigated the biology of pathogen-specific atBCs during acute infection. Here, we performed longitudinal RNA-sequencing and flow cytometry analyses of Plasmodium falciparum (Pf)-specific B cells before and shortly after febrile malaria, with simultaneous analysis of influenza hemagglutinin (HA)-specific B cells as a comparator. B cell receptor-sequencing showed that Pf-specific atBCs, activated B cells (actBCs) and classical memory B cells share clonality and have comparable somatic hypermutation. In response to malaria, Pf-specific atBCs and actBCs expanded and upregulated molecules that mediate B-T cell interactions, suggesting that atBCs respond to T follicular helper (Tfh) cells. Indeed, in the presence of Tfh cells and Staphylococcal enterotoxin B, atBCs of malaria-exposed individuals differentiated into CD38+ antibody-secreting cells in vitro, suggesting that atBCs may actively contribute to humoral immunity to infectious pathogens.One Sentence SummaryThis study shows that atypical B cells actively respond to acute malaria and have the capacity to produce antibodies with T cell help.

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 THU0231 IL-2 DRIVES THE CONVERSION OF T FOLLICULAR HELPER TO T FOLLICULAR REGULATORY CELLS THROUGH EPIGENETIC MODIFICATION IN SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 343.2-343
Author(s):  
H. Hao ◽  
S. Nakayamada ◽  
Y. Kaoru ◽  
N. Ohkubo ◽  
S. Iwata ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Flow Cytometry ◽  
B Cells ◽  
Histone Modifications ◽  
Lupus Erythematosus ◽  
Regulatory Cells ◽  
Systemic Lupus ◽  
Research Support ◽  
Tfh Cells ◽  
Follicular Helper

Background:Systemic lupus erythematosus (SLE) is a complex polygenic autoimmune disease characterized by immune-system aberrations. Among several types of immune cells, T follicular helper (Tfh) cells promote autoantibody production, whereas T follicular regulatory (Tfr) cells suppress Tfh-mediated antibody responses.(1)Objectives:To identify the characteristics of Tfr cells and to elucidate the mechanisms of conversion of Tfh cells to Tfr cells, we probed the phenotype of T helper cells in patients with SLE and underlying epigenetic modifications by cytokine-induced signal transducer and activators of transcription (STAT) family factors.Methods:Peripheral blood mononuclear cells from SLE patients (n=44) and healthy donors (HD; n=26) were analyzed by flow cytometry. Memory Tfh cells were sorted and cultured under stimulation with T cell receptor and various cytokines. Expression of characteristic markers and phosphorylation of STATs (p-STATs) were analyzed by flow cytometry and quantitation PCR. Histone modifications were evaluated by chromatin immunoprecipitation.Results:The proportion of CXCR5+FoxP3+Tfr cells in CD4+T cells tended to increase (2.1% vs 1.7%, p=0.17); however, that of CD4+CD45RA-FoxP3hiactivated Tfr cells in Tfr cells was decreased (4.8% vs 7.1%, p<0.05), while CD4+CD45RA-FoxP3lownon-suppressive Tfr cells was increased (50.1% vs 38.2%, p<0.01) in SLE compared to HD. The percentage of PD-1hiactivated Tfh cells was significantly higher in SLE compared to HD (15.7% vs 5.9%, p<0.01). Furthermore, active patients had a higher ratio of activated Tfh/Tfr cells compared to inactive patients. In vitro study showed that IL-2, but not other cytokines such as TGF-β1, IL-12, IL-27, and IL-35, induced the conversion of memory Tfh cells to functional Tfr cells characterized by CXCR5+Bcl6+Foxp3hipSTAT3+pSTAT5+cells. The loci ofFOXP3at STAT binding sites were marked by bivalent histone modifications. After IL-2 stimulation, STAT5 directly bound on FOXP3 gene loci accompanied by suppressing H3K27me3. Finally, we found that serum level of IL-2 was decreased in SLE and that stimulation with IL-2 suppressed the generation of CD38+CD27+B cells by ex vivo coculture assay using Tfh cells and B cells isolated from human blood.Conclusion:Our findings indicated that the regulatory function of Tfr cells is impaired due to the low ability of IL-2 production and that IL-2 restores the function of Tfr cells through conversion of Tfh cells to Tfr cells in SLE. Thus, the reinstatement of the balance between Tfh and Tfr cells will provide important therapeutic approaches for SLE.References:[1]Deng J, Wei Y, Fonseca VR, et al. T follicular helper cells and T follicular regulatory cells in rheumatic diseases. Nat Rev Rheumatol. 2019; 15 (8): 475-90.Disclosure of Interests: :He Hao: None declared, Shingo Nakayamada Grant/research support from: Mitsubishi-Tanabe, Takeda, Novartis and MSD, Speakers bureau: Bristol-Myers, Sanofi, Abbvie, Eisai, Eli Lilly, Chugai, Asahi-kasei and Pfizer, Yamagata Kaoru: None declared, Naoaki Ohkubo: None declared, Shigeru Iwata: None declared, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin

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