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A Novel Mechanism Of B Cell Activation By Bacteria

The bacterial species Burkholderia ambifaria belongs to the Burkholderia cepacia complex, a group of related bacterial strains, which can cause opportunistic infections in immunocompromised hosts. These bacteria produce various virulence factors, among which are soluble carbohydrate-binding proteins, so-called lectins. The lectin BambL from Burkholderia ambifaria binds to the carbohydrate fucose with high affinity.

Fucose residues are found on various cell surface receptors, for example on the B cell antigen receptor (BCR). This receptor is expressed on B lymphocytes. It consists of two heavy and light chain (HC and LC) molecules, which form the constant and variable regions.

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The variable region binds specific antigens with high affinity, the constant region is non-covalently associated with the Ig╬▒/Ig╬▓ heterodimer, the signal-transducing subunit of the BCR. The constant region furthermore carries carbohydrate residues including fucose. Binding of an antigen to the BCR triggers a signaling cascade downstream of the BCR resulting in B cell activation, their subsequent maturation to plasma cells, and production of large amounts of specific antibodies.

We found that BambL bound to fucosylated epitopes of the BCR thereby activating B cells in vitro. As a read-out for activation, we measured intracellular calcium influx by flow cytometry. Activation was only possible in B cells with an intact surface BCR and its proximal signaling machinery: B cells with genetically inactivated HC, as well as B cells lacking the BCR co-receptor CD19 and the spleen tyrosine kinase (Syk) could not mobilize calcium. Furthermore, prolonged stimulation with BambL led to rapid B cell death, which could be partially averted by the cytokine BAFF.

In vivo, BambL injection resulted in a rapid cellular immune response, characterized by splenomegaly, accumulation of mature follicular B cells and innate immune cells in the spleen. Simultaneously, we observed a depletion of B cells from the bone marrow. On the one hand, we assumed that the accumulation of B cells in the spleen was a result of hyperproliferation of the mature follicular B cells population. On the other hand, the absence of B cells from the bone marrow was most likely due to enhanced programmed cell death at progenitor B cell stage.

Note that in vivo, this phenotype was BCR-independent: mice with Ig╬▒-deficient B cells that lack surface BCR expression, exhibited a similar phenotype as wild type mice. The phenotype subsided within a week in healthy animals. We hypothesized that immunocompromised patients may be unable to mount such a rapid and effective response to pathogenic particles.

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We uncovered a novel mechanism of B cell activation by glycan-targeting bacterial lectins. Therefore, our study opens up the possibility for further in-depth research of host-pathogen interactions.

These findings are described in the article entitled Carbohydrate-dependent B cell activation by fucose-binding bacterial lectins, recently published in the journal Science Signaling.

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