scholarly journals ICAMs support B cell interactions with T follicular helper cells and promote clonal selection

2017 ◽  
Vol 214 (11) ◽  
pp. 3435-3448 ◽  
Author(s):  
Irina Zaretsky ◽  
Ofir Atrakchi ◽  
Roei D. Mazor ◽  
Liat Stoler-Barak ◽  
Adi Biram ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antigen Presentation ◽  
Clonal Expansion ◽  
Cell Interactions ◽  
Antigen Uptake ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Cell Clones ◽  
Wide Range

The germinal center (GC) reaction begins with a diverse and expanded group of B cell clones bearing a wide range of antibody affinities. During GC colonization, B cells engage in long-lasting interactions with T follicular helper (Tfh) cells, a process that depends on antigen uptake and antigen presentation to the Tfh cells. How long-lasting T–B interactions and B cell clonal expansion are regulated by antigen presentation remains unclear. Here, we use in vivo B cell competition models and intravital imaging to examine the adhesive mechanisms governing B cell selection for GC colonization. We find that intercellular adhesion molecule 1 (ICAM-1) and ICAM-2 on B cells are essential for long-lasting cognate Tfh–B cell interactions and efficient selection of low-affinity B cell clones for proliferative clonal expansion. Thus, B cell ICAMs promote efficient antibody immune response by enhancement of T cell help to cognate B cells.

scholarly journals Neoantigen driven B cell and CD4+ T follicular helper cell collaboration promotes robust anti-tumor CD8+ T cell responses

2020 ◽  
Author(s):  
Can Cui ◽  
Jiawei Wang ◽  
Ping-Min Chen ◽  
Kelli A. Connolly ◽  
Martina Damo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Interactions ◽  
Tumor Control ◽  
Cell Responses ◽  
Tfh Cells ◽  
Follicular Helper ◽  
T Follicular Helper Cell

AbstractCD4+ T follicular helper (TFH) cells provide help to B cells, which is critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found TFH cells correlated with GC B cells and with prolonged survival of lung adenocarcinoma (LUAD) patients. To investigate further, we developed an LUAD model, in which tumor cells expressed B-cell- and T-cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells were necessary for tumor control, as were effector CD8+ T cells. The latter were reduced in the absence of T cell-B cell interactions or the IL-21 receptor. IL-21 was produced primarily by TFH cells, development of which required B cells. Moreover, development of tumor-specific TFH cell-responses was also reliant upon tumors that expressed B-cell-recognized neoantigens. Thus, tumor-neoantigens themselves can control the fate decisions of tumor-specific CD4+ T cells by facilitating interactions with tumor-specific B cells.Abstract Figure

scholarly journals Cbl and Cbl-b control the germinal center reaction by facilitating naive B cell antigen processing

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Xin Li ◽  
Liying Gong ◽  
Alexandre P. Meli ◽  
Danielle Karo-Atar ◽  
Weili Sun ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Antigen Processing ◽  
Cell Interaction ◽  
Affinity Maturation ◽  
Antigen Uptake ◽  
Cell Antigen ◽  
Germinal Center Reaction ◽  
Follicular Helper

Antigen uptake and presentation by naive and germinal center (GC) B cells are different, with the former expressing even low-affinity BCRs efficiently capture and present sufficient antigen to T cells, whereas the latter do so more efficiently after acquiring high-affinity BCRs. We show here that antigen uptake and processing by naive but not GC B cells depend on Cbl and Cbl-b (Cbls), which consequently control naive B and cognate T follicular helper (Tfh) cell interaction and initiation of the GC reaction. Cbls mediate CD79A and CD79B ubiquitination, which is required for BCR-mediated antigen endocytosis and postendocytic sorting to lysosomes, respectively. Blockade of CD79A or CD79B ubiquitination or Cbls ligase activity is sufficient to impede BCR-mediated antigen processing and GC development. Thus, Cbls act at the entry checkpoint of the GC reaction by promoting naive B cell antigen presentation. This regulation may facilitate recruitment of naive B cells with a low-affinity BCR into GCs to initiate the process of affinity maturation.

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 Survival and Clonal Expansion of Mutating “Forbidden” (Immunoglobulin Receptor–Deficient) Epstein-Barr Virus–Infected B Cells in Angioimmunoblastic T Cell Lymphoma

2001 ◽  
Vol 194 (7) ◽  
pp. 927-940 ◽  
Author(s):  
Andreas Bräuninger ◽  
Tilmann Spieker ◽  
Klaus Willenbrock ◽  
Philippe Gaulard ◽  
Hans-Heinrich Wacker ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
Clonal Expansion ◽  
Barr Virus ◽  
Cell Clones ◽  
Epstein Barr

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of Epstein-Barr virus (EBV)-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of six patients with frequent EBV+ cells and their rearranged immunoglobulin (Ig) genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or germinal center B cells. EBV+ B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV− B cells showed little tendency for clonal expansion. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of “forbidden” (i.e., Ig-deficient) B cells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells.

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 Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells

2020 ◽  
Author(s):  
Juhee Pae ◽  
Jonatan Ersching ◽  
Tiago B. R. Castro ◽  
Marta Schips ◽  
Luka Mesin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Clonal Expansion ◽  
Affinity Maturation ◽  
Cyclin D3 ◽  
Dark Zone ◽  
Follicular Helper ◽  
Cell Cycle Regulator Cyclin

AbstractDuring affinity maturation, germinal center (GC) B cells alternate between proliferation and so-matic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively-selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by “inertia.” We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma-associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, to clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.

scholarly journals CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuhong Chen ◽  
Mei Yu ◽  
Yongwei Zheng ◽  
Guoping Fu ◽  
Gang Xin ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
T Cell Subsets ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Autoantibody Production ◽  
Tfh Cells ◽  
Follicular Helper

Abstract Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.

scholarly journals OP0024 DECREASED LEVELS OF T FOLLICULAR HELPER (CD4+CXCR5+) CELLS AND CD27+CD38+ AND CD27+CD38- B CELLS IN ANKYLOSING SPONDYLITIS PATIENTS CORRELATE WITH MARKER OF INFLAMMATION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 13.2-14
Author(s):  
H. Forsblad-D’elia ◽  
U. Hellman ◽  
A. Kumar ◽  
K. Lejon
Keyword(s):  
Ankylosing Spondylitis ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Female Patients ◽  
Tfh Cells ◽  
Follicular Helper ◽  
B Cell Subsets

Background:The role of different lymphocyte subsets in ankylosing spondylitis (AS) is still to be elucidated. It has previously been reported contradictory data concerning the levels of T Follicular Helper (TFH) cells and differentiated B cells in peripheral blood of AS patients. In addition, the connection to disease related parameters is still to be fully revealed.Objectives:The purpose of this study was to investigate the level of CD4+TFH cells and CD27+CD38+/CD38- B cells in patients with AS from northern Sweden and to compare the levels with age and sex-matched controls. We also studied associations between these cell subsets and disease related factors.Methods:Peripheral blood mononuclear cells (PBMSc) from a cohort of 50 patients with AS from Region Västerbotten (mean age 52±9.1 years, 33 (66 %) men, 50 (100 %) HLAB27 positive) and 50 pair wise matched blood donor controls (mean age 54±8.8 years, 33 (66 %) men) were stained with a combination of antibodies allowing for the detection of CD27, CD38, CD19, CD3, CD4 and CXCR5 markers and analyzed by flow cytometry. In addition, the patient with AS were examined with spinal x-ray for radiographic alterations assessed with mSASSS. CRP and ESR were measured and physical function and disease activity were registered with BASMI and BASFI respectively ASDAS-CRP and BASDAI.Results:When comparing AS patients and controls pair wise, we observed on average a 50% reduction of TFH (CD3+CD4+CXCR5+) cells among CD45+ lymphocytes in PBMCs from patients (p=0,000008). Furthermore, a 20-30% reduction among memory/plasma cells (CD19+CD27+CD38+ and CD19+CD27+CD38-) among CD45+ lymphocytes in PBMCs from patients (p=0,002 and p=0,007 respectively). For female patients a correlation between TFH and ESR (Rs=-0,551 p=0,022) was observed. Moreover, negative correlations between the two B cell subsets (CD19+CD27+CD38+ and CD19+CD27+CD38-) and ESR were observed for female patients (Rs =–0,476 p=0,053 and Rs =–0,522 p=0,032 respectively).Conclusion:TFH cells was reduced in AS patients and this reduction correlated with a reduction in differentiated (CD27+CD38+ and CD27+CD38-) B cells. In addition, the inflammation marker ESR was negatively correlated with TFH as well as with the differentiated B cell subsets in female patients. Our observations indicates a role of the humoral immune response in AS.Disclosure of Interests:None declared

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 Can follicular helper T cells be targeted to improve vaccine efficacy?

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 88 ◽  
Author(s):  
Michelle A. Linterman ◽  
Danika L. Hill
Keyword(s):  
T Cells ◽  
B Cells ◽  
Plasma Cells ◽  
Subsequent Infection ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Cell Clones ◽  
Rational Vaccine Design ◽  
Selection Of

The success of most vaccines relies on the generation of antibodies to provide protection against subsequent infection; this in turn depends on a robust germinal centre (GC) response that culminates in the production of long-lived antibody-secreting plasma cells. The size and quality of the GC response are directed by a specialised subset of CD4+T cells: T follicular helper (Tfh) cells. Tfh cells provide growth and differentiation signals to GC B cells and mediate positive selection of high-affinity B cell clones in the GC, thereby determining which B cells exit the GC as plasma cells and memory B cells. Because of their central role in the production of long-lasting humoral immunity, Tfh cells represent an interesting target for rational vaccine design.

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