Germinal center B cells recognize antigen through a specialized immune synapse architecture.

Carla R Nowosad,Katelyn M Spillane,Pavel Tolar

doi:10.1038/ni.3458

Carla R Nowosad, Katelyn M Spillane + Show 1 more

Open Access

https://doi.org/10.1038/ni.3458

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Abstract

B cell activation is regulated by B cell antigen receptor (BCR) signaling and antigen internalization in immune synapses. Using large-scale imaging across B cell subsets, we show that in contrast to naive and memory B cells, which gathered antigen towards the synapse center before internalization, germinal center (GC) B cells extracted antigen by a distinct pathway using small peripheral clusters. Both naive and GC B cell synapses required proximal BCR signaling, but GC cells signaled less through the protein kinase C-β (PKC-β)–NF-κB pathway and produced stronger tugging forces on the BCR, thereby more stringently regulating antigen binding. Consequently, GC B cells extracted antigen with better affinity discrimination than naive B cells, suggesting that specialized biomechanical patterns in B cell synapses regulate T-cell dependent selection of high-affinity B cells in GCs.

Highlights

Antibody responses are triggered when naive B cells bind antigen on the surfaces of antigenpresenting cells (APCs) such as subcapsular macrophages[1,2,3] and dendritic cells[4,5]
Through large-scale quantitative analysis, we show here that all naive and memory B cell subsets formed such canonical synapses, with a developmental increase in antigen centralization from transitional to follicular B cells
Cytoskeleton-dependent antigen centralization has been associated with regulation of B cell antigen receptor (BCR) signaling and autoimmunity[28,29,30], suggesting that the degree of antigen centralization could control B cell activation in a subset-specific manner

Summary

Introduction

Antibody responses are triggered when naive B cells bind antigen on the surfaces of antigenpresenting cells (APCs) such as subcapsular macrophages[1,2,3] and dendritic cells[4,5] This initiates B cell antigen receptor (BCR) signaling and the formation of an immune synapse. GC B cells containing somatic mutations that improve affinity for antigen acquire more antigen from FDCs than lower affinity GC B cells do, resulting in a selective advantage during T cell-dependent selection and subsequent proliferation in the GC dark zone[17,18] This selection requires NF-κB activation, presumably induced by T cellderived CD40 signaling[19,20]. Despite the importance of GC B cell antigen acquisition from synapses with FDCs, GC B cell synapse formation and its contribution to affinity-dependent antigen internalization have not been investigated

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