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Optimal B cell activation involves B cells spreading over the antigen-bearing membrane and then contracting to collect bound antigen into a central aggregate.

It is easy to imagine how a B cell can bind and internalize soluble antigens through B-cell receptors (BCRs) and be activated depending on the affinity of the interaction. But it is less clear how B cells acquire and sense the affinity of membrane-associated antigens, which are known to be highly effective in driving B-cell activation. By elegant imaging and computer modelling, Facundo Batista and colleagues show that, for optimal B-cell activation, the B cell must spread across antigen-bearing membranes and then contract, thereby collecting the antigen–BCR complexes into a central cluster. How effectively this process occurs depends on the strength of the antigen–BCR interaction.


A scanning electron microscopy image of a B cell spreading on the surface of a cell displaying its cognate antigen. Image courtesy of S. Fleire, London Research Institute, UK.

In a similar manner to the intimate interaction between T cells and antigen-presenting cells (APCs), when a B cell recognizes antigens tethered on a cell surface, a cluster of BCRs and their ligands forms at the contact site. At the same time, other membrane proteins are recruited and reorganized to form an immunological synapse.

To follow the early morphological changes of B cells during activation, the authors studied, by electron microscopy, the interaction of B cells that expressed a transgenic BCR specific for hen-egg lysozyme (HEL) with target cells that expressed a membrane-tethered form of the HEL antigen. The authors observed that on recognition of antigen, the B cell rapidly (2–4 min after contact) spreads across the target cell membrane before gradually contracting. This cellular response was dependent on recognition of the specific antigen, signal transduction through the BCR and actin polymerization. Importantly, the antigen–BCR complexes were initially gathered into microclusters before being concentrated in a central cluster, from where the B cell could efficiently acquire the antigen.

Using a set of mutant HEL proteins that have a range of affinities for the transgenic BCR, the authors next showed that the level of the B-cell response was influenced by the density of the antigen and the affinity of the antigen for the BCR. Moreover, the amount of antigen that was taken up by the B cell and the subsequent ability of the B cell to present the antigen to T cells were proportional to the total amount of antigen accumulated in the central cluster.

On the basis of these observations the authors generated a computer model that reproduced the empirical data. The model showed that this antigen-collection process allows the B cells to discriminate between ligands of different affinity. So, high-affinity interactions favour further B-cell spreading and exposure to membrane-bound ligands before contraction and collection. By contrast, low-affinity interactions result in inefficient spreading and low levels of antigen collection and therefore reduced B-cell activation.

Lucy Bird

References

Fleire, S. J. et al. B cell ligand discrimination through a spreading and contraction response. Science 312, 738–741 (2006) | Article | PubMed |
Harnett, M. M. B cells spread and gather. Science 312, 709–710 (2006) | Article | PubMed |