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.

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

Reduced expression of hematopoietic progenitor kinase 1 in T follicular helper cells causes autoimmunity of systemic lupus erythematosus

Lupus ◽  
2021 ◽  
pp. 096120332110625
Author(s):  
Huilin Zhang ◽  
Yuming Xie ◽  
Junke Huang ◽  
Danhong Luo ◽  
Qing Zhang
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Damage Index ◽  
Enzyme Linked Immunosorbent Assay ◽  
Systemic Lupus ◽  
Hematopoietic Progenitor ◽  
Protein Levels ◽  
Tfh Cells ◽  
Follicular Helper

Backgroud T follicular helper (Tfh) cells have been discovered to be the main CD4+ T cells assisting B cells to produce antibody. They are over activated in patients with systemic lupus erythematosus (SLE) and consequently lead to excessive immunity. Hematopoietic progenitor kinase 1 (HPK1) negatively regulates T cell-mediated immune responses and TCR signal. This study aimed to investigate the roles of HPK1 in SLE Tfh cells. Methods HPK1 mRNA and protein levels in Tfh cells were measured by real-time quantitative PCR and western blot analysis, respectively. The production of IL-21, B cell−activating factor (BAFF), interferon γ (IFNγ), IL-17A, IgM, IgG1, IgG2, and IgG3 were analyzed using enzyme linked immunosorbent assay. Tfh cells proliferation was evaluated with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results HPK1 mRNA and protein levels were significantly reduced in SLE Tfh cells, and negatively correlated with SLE disease activity index (SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for SLE (SDI). Knocking down HPK1 with siRNA in normal Tfh cells greatly elevated Tfh cells proliferation and secretions of IL-21, BAFF, IFNγ, IgG1, IgG2, and IgG3. There were no marked alterations in IL-17A and IgM productions. The opposite effects were observed in SLE Tfh cells transfected with HPK1 overexpressing plasmid: Tfh cells proliferation and productions of IL-21, BAFF, IFNγ, IgG1, IgG2, and IgG3 were all alleviated. And there were no significant changes in IL-17A and IgM levels. Conclusion Our results suggest for the first time that inhibited expression of HPK1 in SLE Tfh cells leading to Tfh cells overactivation and B cells overstimulation, subsequently, the onset and progression of SLE.

scholarly journals IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses

2010 ◽  
Vol 207 (2) ◽  
pp. 353-363 ◽  
Author(s):  
Michelle A. Linterman ◽  
Laura Beaton ◽  
Di Yu ◽  
Roybel R. Ramiscal ◽  
Monika Srivastava ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Formation ◽  
Affinity Maturation ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Early Memory ◽  
Bone Marrow Chimeras ◽  
Follicular Response

During T cell–dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell–intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell–autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1+ GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.

scholarly journals Antigen-presenting ILC3 regulate T cell–dependent IgA responses to colonic mucosal bacteria

2019 ◽  
Vol 216 (4) ◽  
pp. 728-742 ◽  
Author(s):  
Felipe Melo-Gonzalez ◽  
Hana Kammoun ◽  
Elza Evren ◽  
Emma E. Dutton ◽  
Markella Papadopoulou ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Antigen Presentation ◽  
Immunoglobulin A ◽  
Lymphoid Cells ◽  
Host Interactions ◽  
Commensal Microbiota ◽  
Follicular Helper ◽  
Cell Class ◽  
Antigen Presenting

Intestinal immune homeostasis is dependent upon tightly regulated and dynamic host interactions with the commensal microbiota. Immunoglobulin A (IgA) produced by mucosal B cells dictates the composition of commensal bacteria residing within the intestine. While emerging evidence suggests the majority of IgA is produced innately and may be polyreactive, mucosal-dwelling species can also elicit IgA via T cell–dependent mechanisms. However, the mechanisms that modulate the magnitude and quality of T cell–dependent IgA responses remain incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3) regulate steady state interactions between T follicular helper cells (TfH) and B cells to limit mucosal IgA responses. ILC3 used conserved migratory cues to establish residence within the interfollicular regions of the intestinal draining lymph nodes, where they act to limit TfH responses and B cell class switching through antigen presentation. The absence of ILC3-intrinsic antigen presentation resulted in increased and selective IgA coating of bacteria residing within the colonic mucosa. Together these findings implicate lymph node resident, antigen-presenting ILC3 as a critical regulatory checkpoint in the generation of T cell–dependent colonic IgA and suggest ILC3 act to maintain tissue homeostasis and mutualism with the mucosal-dwelling commensal microbiota.

scholarly journals Antigen recognition. V. Requirement for histocompatibility between antigen-presenting cell and B cell in the response to a thymus-dependent antigen, and lack of allogeneic restriction between T and B cells.

1981 ◽  
Vol 154 (3) ◽  
pp. 676-687 ◽  
Author(s):  
E Nisbet-Brown ◽  
B Singh ◽  
E Diener
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Fetal Liver ◽  
T And B Cells ◽  
Antigen Presenting Cell ◽  
Experimental Conditions ◽  
Left Hand ◽  
Antigen Presenting

The restrictions imposed by the major histocompatibility complex on T-B-antigen-presenting cell (APC) interactions were studied with an in vivo adoptive transfer system, using mutually tolerant T and B cells taken from one-way fetal liver chimeras. It was found that the B cells and adoptive recipient (which provides APC function) have to share determinants encoded by the left-hand end of the H-2 complex for cooperation, whereas there is apparently no such requirement for T-B cell syngeneicity. Suppression arising from allogeneic effects between the host and the transferred T or B cells was excluded by the use of tolerant as well as normal adoptive recipients; both were functionally equivalent. We conclude that under experimental conditions, unrestricted helper T cell function and concurrent APC-B cell genetic restriction can be demonstrated in vivo.

Establishment of An Angioimmunoblastic T-Cell Lymphoma (AITL) Model in the NOG Mouse

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5207-5207
Author(s):  
Asahi Ito ◽  
Takashi Ishida ◽  
Fumihiko Sato ◽  
Fumiko Mori ◽  
Ayako Masaki ◽  
...  
Keyword(s):  
B Cells ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Treatment Modalities ◽  
Medium Size ◽  
Double Immunostaining ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Novel Treatment ◽  
Nog Mice

Abstract Abstract 5207 The aim of the present study was to establish a murine AITL model. We inoculated cells from affected LN of an AITL patient intraperitoneally into NOG mice. Hepatosplenomegaly developed in these animals about 2 months later, and normal splenic architecture was replaced by multi-focal deposit of lymphocytes and numerous blood vessels. Some of the former consisted of AITL cells characterized by small to medium size, and clear to pale cytoplasm. The remaining lymphocytes were non-neoplastic reactive cells including CD8-positive cells, B cells, and plasma cells. Double immunostaining revealed that the neoplastic cells were positive for both UCHL-1 (CD45RO) and BCL-6. In addition, significant levels of human IgG/A/M were detected in these animals. The AITL cells engrafted in the NOG mice indeed functioned as follicular helper T (Tfh) cells and induced antibody production by B-cells, consistent with recent evidence that AITL is a neoplasm originating from Tfh cells. These clinical and histological features in the mice are almost identical to those seen in AITL patients. Cells from spleens of affected animals could be serially transplanted, with enrichment of the AITL cells together with reduction of the reactive cells at each passage. This phenomenon might reflect the progressive nature of AITL. TCRB analysis demonstrated that the AITL clone in the mice was identical to that from the donating patient. This is the first mouse model of AITL, and could be a powerful tool for investigating, and developing novel treatment modalities for this type of lymphoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IL-12 receptor β1 deficiency alters in vivo T follicular helper cell response in humans

Blood ◽  
2013 ◽  
Vol 121 (17) ◽  
pp. 3375-3385 ◽  
Author(s):  
Nathalie Schmitt ◽  
Jacinta Bustamante ◽  
Laure Bourdery ◽  
Salah Eddine Bentebibel ◽  
Stephanie Boisson-Dupuis ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Response ◽  
Memory B Cells ◽  
Helper Cell ◽  
Tfh Cells ◽  
Control Subjects ◽  
Follicular Helper ◽  
Key Points ◽  
T Follicular Helper Cell

Key Points IL-12Rβ1–deficient subjects displayed substantially less circulating memory Tfh and memory B cells than control subjects. The IL-12–STAT4 axis is associated with the development and functions of Tfh cells in vivo in humans.

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