Germinal center B cells govern their own fate via antibody feedback

Zhang, Yang; Meyer‐Hermann, Michael; George, Laura; Figge, Marc Thilo; Khan, Mahmood; Goodall, Margaret; Young, Stephen P.; Reynolds, Adam Thomas; Falciani, Francesco; Waisman, Ari; Notley, Clare A.; Ehrenstein, Michael R.; Kosco‐Vilbois, Marie H.; Toellner, Kai‐Michael

doi:10.1084/jem.20120150

Cited by 251 publications

(363 citation statements)

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“…A sign of B-cell function is the formation of germinal centers (GCs) in follicles within the spleen and other lymphoid organs, such as Peyer's patches (Pp) and lymph nodes (LNs) (20). In GCs, B cells proliferate and differentiate to produce higher affinity antibodies and switch isotypes (21,22). We found that KO mice had an increased frequency of IgAexpressing GC B cells in Pp compared with WT controls, as well as a variable but, on average, twofold reduction in IgG1-expressing B cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Clathrin light chains’ role in selective endocytosis influences antibody isotype switching

Majeed

Evans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Clathrin, a cytosolic protein composed of heavy and light chain subunits, assembles into a vesicle coat, controlling receptor-mediated endocytosis. To establish clathrin light chain (CLC) function in vivo, we engineered mice lacking CLCa, the major CLC isoform in B lymphocytes, generating animals with CLC-deficient B cells. In CLCa-null mice, the germinal centers have fewer B cells, and they are enriched for IgA-producing cells. This enhanced switch to IgA production in the absence of CLCa was attributable to increased transforming growth factor β receptor 2 (TGFβR2) signaling resulting from defective endocytosis. Internalization of C-X-C chemokine receptor 4 (CXCR4), but not CXCR5, was affected in CLCa-null B cells, and CLC depletion from cell lines affected endocytosis of the δ-opioid receptor, but not the β2-adrenergic receptor, defining a role for CLCs in the uptake of a subset of signaling receptors. This instance of clathrin subunit deletion in vertebrates demonstrates that CLCs contribute to clathrin’s role in vivo by influencing cargo selectivity, a function previously assigned exclusively to adaptor molecules.

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Section: Resultsmentioning

confidence: 99%

Clathrin light chains’ role in selective endocytosis influences antibody isotype switching

Majeed

Evans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Fas is highly expressed on activated B cells, particularly in the germinal center, where it mediates the deletion of autoreactive or unproductive somatic hypermutated B cells (12)(13)(14). Fas, as well as its ligand FasL, play critical roles in B-cell apoptosis.…”

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confidence: 99%

Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas

Kong¹,

Yang²,

Xu³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Humoral immunity involves multiple checkpoints during B-cell development, maturation, and activation. The cell death receptor CD95/Fas-mediated apoptosis plays a critical role in eliminating the unwanted activation of B cells by self-reactive antigens and in maintaining B-cell homeostasis through activation-induced B-cell death (AICD). The molecular mechanisms controlling AICD remain largely undefined. Herein, we show that the E3 ubiquitin ligase Hrd1 protected B cells from activation-induced cell death by degrading the death receptor Fas. Hrd1-null B cells exhibited high Fas expression during activation and rapidly underwent Fas-mediated apoptosis, which could be largely inhibited by FasL neutralization. Fas mutation in Hrd1 KO mice abrogated the increase in B-cell AICD. We identified Hrd1 as the first E3 ubiquitin ligase of the death receptor Fas and Hrd1-mediated Fas destruction as a molecular mechanism in regulating B-cell immunity.Hrd1 | Fas | B cells | ubiquitination B -cell immunity involves several checkpoints, which are important to orchestrate and balance survival and apoptotic signals and control the quality and size of the B-cell compartment (1, 2). The earliest steps in B-cell development occur in the bone marrow, where assembly of the pre-B-cell receptor (pre-BCR) followed by the mature BCR occurs in distinct stages. Once the mature BCR is expressed, B lymphocytes then progress into the immature B-cell stage, where further selection checkpoints occur before the immature B cells transition to the periphery and mature into circulating B cells (2, 3). Mature B cells are maintained through tonic BCR, CD40, and B-cell-activating factor receptor (BAFFR) signaling (4). Activation by cross-linking the BCR leads to rapid proliferation, somatic hypermutation, and further differentiation of B cells (5, 6). The expansion of activated B-cell compartment is subsequently downmodulated through activation-induced cell death (AICD) (7,8).The death receptor Fas has been identified as a key regulator of AICD of B cells (9-11). Fas is highly expressed on activated B cells, particularly in the germinal center, where it mediates the deletion of autoreactive or unproductive somatic hypermutated B cells (12)(13)(14). Fas, as well as its ligand FasL, play critical roles in B-cell apoptosis. The selective removal of Fas from activated B cells results in lupus-like disease and autoantibody production (15-17). It has been a widely accepted view that the Fas/FasL mutations result in, at least in part, a failure to eliminate self-reactive GC B cells in autoimmune patients and animal models (12, 18). However, more recent studies show that FAS is in fact not required for the elimination of self-reactive GC B cells. Instead, Fas inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation and survived despite losing antigen reactivity (8). Nevertheless, it is clear that Fasmediated B-cell death is critically involved in B-cell-mediated autoimmune diseases. However, the molecular...

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“…Three different affinity-dependent mechanisms with impact on B cell selection and differentiation were compared: DND, affinity-dependent dynamic increase of the number of B cell divisions; DSH, affinitydependent dynamic downregulation of somatic hypermutation (17); and AFB, Ab feedback onto the GC reaction (21). Although DND and DSH both represent mechanisms on the level of individual interactions between B and T cells, which depend on the previously collected, processed, and presented amount of Ag, AFB represents the idea that Abs generated by the GC output increase B cell competition for Ag by coverage of the Ag presented on FDCs.…”

Section: Resultsmentioning

confidence: 99%

“…The novel modeling framework for GC reactions presented in this article can be considered as a combination of the LEDA model (17) and a dynamic description of generated Abs including Ab feedback (AFB) onto the GC dynamics derived from chemical binding kinetics (21). The combined model was further extended to include dynamic and affinity-dependent number of B cell divisions (DND), and dynamic affinity-dependent somatic hypermutation probability (DSH).…”

Section: General Modeling Frameworkmentioning

confidence: 99%

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Overcoming the Dichotomy of Quantity and Quality in Antibody Responses

Meyer‐Hermann

2014

The Journal of Immunology

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Germinal centers (GCs) are specialized environments in which B cells mutate their BCR to identify new Abs with high affinity to a challenging Ag. B cells are selected in an evolutionary process of multiple rounds of mutation and selection. In the past decade, mechanisms of B cell migration, division, mutation, selection, and final differentiation have been extensively studied. Thereby, modulations of these mechanisms either optimize the quality, in terms of affinity, or the quantity of generated Abs, but never both, leading to an unclear effect on the overall efficiency of the Ab response. In this article, we predict with mathematical models that an affinity-dependent number of GC B cell divisions overcomes the dichotomy of quality and quantity, and has to be considered as a good target for immune interventions, in particular, in the elderly population with poor GC responses.

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Germinal center B cells govern their own fate via antibody feedback

Abstract: High-affinity antibodies reenter germinal centers (GCs) and limit antigen access, thus causing sustained directional evolution in GCs toward higher-affinity antibody production.

Cited by 251 publications

References 36 publications

Clathrin light chains’ role in selective endocytosis influences antibody isotype switching

Clathrin light chains’ role in selective endocytosis influences antibody isotype switching

Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas

Overcoming the Dichotomy of Quantity and Quality in Antibody Responses

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