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 The Development of Optimally Responsive Plasmodium-specific CD73+CD80+ IgM+ Memory B cells Requires Intrinsic BCL6 expression but not CD4+ Tfh cells

2019 ◽  
Author(s):  
Gretchen Harms Pritchard ◽  
Akshay T. Krishnamurty ◽  
Jason Netland ◽  
E. Nicole Arroyo ◽  
Kennidy K. Takehara ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Plasma Cells ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Effector Cells ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Bcl6 Expression

SummaryHumoral immunity depends upon the development of long-lived, antibody-secreting plasma cells and rapidly responsive memory B cells (MBCs). The differentiation of high affinity, class-switched MBCs after immunization is critically dependent upon BCL6 expression in germinal center (GC) B cells and CD4+ T follicular helper (Tfh) cells. It is less well understood how more recently described MBC subsets are generated, including the CD73+CD80+ IgM+ MBCs that initially form antibody-secreting effector cells in response to a secondary Plasmodium infection. Herein, we interrogated how BCL6 expression in both B and CD4+ T cells influenced the formation of heterogeneous Plasmodium-specific MBC populations. All Plasmodium-specific CD73+CD80+ MBCs required BCL6 expression for their formation, suggesting germinal center dependence. Further dissection of the CD4+ T and B cell interactions however revealed that somatically hypermutated CD73+CD80+ IgM+ MBCs can form not only in the absence of germinal centers, but also in the absence of CXCR5+ CD4+ Tfh cells.

scholarly journals Intrinsic properties of human germinal center B cells set antigen affinity thresholds

2018 ◽  
Vol 3 (29) ◽  
pp. eaau6598 ◽  
Author(s):  
Kihyuck Kwak ◽  
Nicolas Quizon ◽  
Haewon Sohn ◽  
Avva Saniee ◽  
Javier Manzella-Lapeira ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Synapse Formation ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Intrinsic Properties ◽  
High Affinity ◽  
Follicular Helper ◽  
Bcr Signaling ◽  
Engagement And Disengagement

Protective antibody responses to vaccination or infection depend on affinity maturation, a process by which high-affinity germinal center (GC) B cells are selected on the basis of their ability to bind, gather, and present antigen to T follicular helper (Tfh) cells. Here, we show that human GC B cells have intrinsically higher-affinity thresholds for both B cell antigen receptor (BCR) signaling and antigen gathering as compared with naïve B cells and that these functions are mediated by distinct cellular structures and pathways that ultimately lead to antigen affinity– and Tfh cell–dependent differentiation to plasma cells. GC B cells bound antigen through highly dynamic, actin- and ezrin-rich pod-like structures that concentrated BCRs. The behavior of these structures was dictated by the intrinsic antigen affinity thresholds of GC B cells. Low-affinity antigens triggered continuous engagement and disengagement of membrane-associated antigens, whereas high-affinity antigens induced stable synapse formation. The pod-like structures also mediated affinity-dependent antigen internalization by unconventional pathways distinct from those of naïve B cells. Thus, intrinsic properties of human GC B cells set thresholds for affinity selection.

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 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.

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 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 Frontiers of Autoantibodies in Autoimmune Disorders: Crosstalk Between Tfh/Tfr and Regulatory B Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Tingting Ding ◽  
Rui Su ◽  
Ruihe Wu ◽  
Hongwei Xue ◽  
Yanyan Wang ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Diseases ◽  
Treg Cells ◽  
Regulatory B Cells ◽  
Cellular Mechanisms ◽  
Autoantibody Production ◽  
Cell Responses ◽  
Tfh Cells ◽  
Follicular Helper

Balance of Tfh/Tfr cell is critically important for the maintenance of immune tolerance, as evidenced by the fact that T follicular helper (Tfh) cells are central to the autoantibodies generation through providing necessary help for germinal center (GC) B cells, whereas T follicular regulatory (Tfr) cells significantly inhibit autoimmune inflammation process through restraining Tfh cell responses. However, signals underlying the regulation of Tfh and Tfr cells are largely undefined. Regulatory B cells (Bregs) is a heterogeneous subpopulation of B cells with immunosuppressive function. Considerable advances have been made in their functions to produce anti‐inflammatory cytokines and to regulate Th17, Th1, and Treg cells in autoimmune diseases. The recent identification of their correlations with dysregulated Tfr/Tfh cells and autoantibody production makes Bregs an important checkpoint in GC response. Bregs exert profound impacts on the differentiation, function, and distribution of Tfh and Tfr cells in the immune microenvironment. Thus, unraveling mechanistic information on Tfh-Breg and Tfr-Breg interactions will inspire novel implications for the establishment of homeostasis and prevention of autoantibodies in diverse diseases. This review summarizes the dysregulation of Tfh/Tfr cells in autoimmune diseases with a focus on the emerging role of Bregs in regulating the balance between Tfh and Tfr cells. The previously unsuspected crosstalk between Bregs and Tfh/Tfr cells will be beneficial to understand the cellular mechanisms of autoantibody production and evoke a revolution in immunotherapy for autoimmune diseases.

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