Germinal Center B Cell Dynamics

Mesin, Luka; Ersching, Jonatan; Victora, Gabriel D.

doi:10.1016/j.immuni.2016.09.001

Cited by 780 publications

(895 citation statements)

References 147 publications

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“…The ability to simultaneously identify and analyze endogenous polyclonal antigen-specific CD4 + T cells and B cells responding to Plasmodium has revealed a profound effect of innate immune control of parasitemia. Control of parasitemia is important for timely development of the GC response, a response critical for both the efficient generation of high-affinity antibodies and durable immune memory (59)(60)(61)(62). Furthermore, our ability to track parasitemia throughout the course of infection combined with the potential to rapidly clear blood-stage infection with atovaquone provided us with an elegant system in which the effects of innate control of parasite burden could be disentangled from the effects of early innate signals on the adaptive immune response.…”

Section: Discussionmentioning

confidence: 99%

“…To examine antigen-specific CD4 + T cells responding to infection, P. yoelii were generated that constitutively express the Lymphocytic choriomeningitis virus-derived (LCMV-derived) glycoprotein (GP) epitope (GP [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] ). This allows for the identification and analysis of antigen-specific CD4 + T cells using previously described GP66:I-A B tetramer enrichment strategies (16).…”

Section: Introductionmentioning

confidence: 99%

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cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

Hahn¹,

Butler²,

Lindner³

et al. 2018

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

Hahn¹,

Butler²,

Lindner³

et al. 2018

JCI Insight

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“…The high levels of IL-7R expressed by CD4 ϩ T cells may indicate the relevance of these cells to the ability of IL-7 to expand levels of Tfh cells and then to initiate the process of differentiation of augmented B cells into GC-derived B cells. These cells subsequently differentiate into Bmem and PCs after an extensive selection step (47). The role of IL-7 in the development of Bmem and PCs in the context of RABV-mediated immune responses appears to be important, but the details of this process remain to be fully explored.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Interleukin-7 Extends the Humoral Immune Response Induced by Rabies Vaccination

Zhou

Luo

et al. 2017

J Virol

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Rabies continues to present a public health threat in most countries of the world. The most efficient way to prevent and control rabies is to implement vaccination programs for domestic animals. However, traditional inactivated vaccines used in animals are costly and have relatively low efficiency, which impedes their extensive use in developing countries. There is, therefore, an urgent need to develop single-dose and long-lasting rabies vaccines. However, little information is available regarding the mechanisms underlying immunological memory, which can broaden humoral responses following rabies vaccination. In this study, a recombinant rabies virus (RABV) that expressed murine interleukin-7 (IL-7), referred to here as rLBNSE-IL-7, was constructed, and its effectiveness was evaluated in a mouse model. rLBNSE-IL-7 induced higher rates of T follicular helper (Tfh) cells and germinal center (GC) B cells from draining lymph nodes (LNs) than the parent virus rLBNSE. Interestingly, rLBNSE-IL-7 improved the percentages of long-lived memory B cells (Bmem) in the draining LNs and plasma cells (PCs) in the bone marrow (BM) for up to 360 days postimmunization (dpi). As a result of the presence of the long-lived PCs, it also generated prolonged virus-neutralizing antibodies (VNAs), resulting in better protection against a lethal challenge than that seen with rLBNSE. Moreover, consistent with the increased numbers of Bmem and PCs after a boost with rLBNSE, rLBNSE-IL-7-immunized mice promptly produced a more potent secondary anti-RABV neutralizing antibody response than rLBNSE-immunized mice. Overall, our data suggest that overexpressing IL-7 improved the induction of long-lasting primary and secondary antibody responses post-RABV immunization.IMPORTANCE Extending humoral immune responses using adjuvants is an important method to develop long-lasting and efficient vaccines against rabies. However, little information is currently available regarding prolonged immunological memory post-RABV vaccination. In this study, a novel rabies vaccine that expressed murine IL-7 was developed. This vaccine enhanced the numbers of Tfh cells and the GC responses, resulting in upregulated quantities of Bmem and PCs. Moreover, we found that the long-lived PCs that were elicited by the IL-7-expressing recombinant virus (rLBNSE-IL-7) were able to sustain VNA levels much longer than those elicited by the parent rLBNSE virus. Upon reexposure to the pathogen, the longevous Bmem, which maintained higher numbers for up to 360 dpi with rLBNSE-IL-7 compared to rLBNSE, could differentiate into antibody-secreting cells, resulting in rapid and potent secondary production of VNAs. These results suggest that the expression of IL-7 is beneficial for induction of potent and long-lasting humoral immune responses.KEYWORDS IL-7, humoral immunity, rabies virus

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“…GC B cells with higher affinity for Ag undergo selection in the LZ and then move into the DZ, where they proliferate and undergo somatic hypermutation (Allen et al, 2007; Victora et al, 2010; Victora and Nussenzweig, 2012). Through ubiquitination and rapid degradation of major histocompatibility complex II (MHCII)-Ag complexes, GC B cells refresh their pool of MHCII molecules and reenter into the LZ for another round of Ag acquisition and presentation (Bannard et al, 2016; Victora et al, 2010; Mesin et al, 2016). Affinity-mediated selection of GC B cells is based on competition for Ag and T cell help, but the individual roles of the signals provided by B cell receptor (BCR) engagement and follicular helper T cells (Tfhs) in promoting selection are not fully understood (Shlomchik and Weisel, 2012).…”

Section: Introductionmentioning

confidence: 99%

B Cell Receptor Crosslinking Augments Germinal Center B Cell Selection when T Cell Help Is Limiting

Turner

Grigorova

2018

Cell Reports

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SUMMARY Antigen-dependent engagement of germinal center (GC) B cell receptors (BCRs) promotes antigen internalization and presentation for follicular helper T cells. However, whether BCR signaling is critical or synergistic with T cell help for GC B cell selection or differentiation is unclear. Here, by adapting an experimental approach that enables independent delivery of BCR-crosslinking antigen or T cell help to GC B cells in vivo, we showed that T cell help was sufficient to induce GC B cell expansion and plasmablast formation. However, although BCR crosslinking could not by itself promote GC B cell selection or differentiation, it could synergize with T cell help to enhance the GC and plasmablast responses when T cell help was limiting. These findings indicate that GC B cells can integrate variable inputs from T cell help and BCR signaling in vivo for an optimal process of selection and differentiation, critical for potent long-term humoral immunity.

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Germinal Center B Cell Dynamics

Cited by 780 publications

References 147 publications

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

Overexpression of Interleukin-7 Extends the Humoral Immune Response Induced by Rabies Vaccination

B Cell Receptor Crosslinking Augments Germinal Center B Cell Selection when T Cell Help Is Limiting

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