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Rebuilding immunoreceptors reveals their mode of activation
10 September 2010
Just 110 years ago in 1900, Paul Ehrlich, one of the founding fathers of modern immunology, gave the Croonian Lecture to the Royal Society in London “On Immunity with Special Reference to Cell Life”. In this lecture he explained his “side-chain theory” proposing for the first time a receptor-ligand interaction as the basis for the immune reaction against bacterial toxins. This theory fell in discredit when it was found that our immune system does not only react against toxins but against a diverse universe of different molecular structures that are foreign to our body. Since then, immunologists have made many important discoveries better describing the cells and molecules of our immune system. It is now known that B lymphocytes are the cells that produce antibodies once they are activated by the binding of a foreign molecule (called antigen) to the antigen receptor. Antigens can be a virus, a bacterial molecule or any higher-structured molecule foreign to our body. Other receptors on the cell surface are only activated when they bind to a specific ligand molecule that brings the receptor into the proper conformation required for signalling. How then can the B cell antigen receptor (BCR) achieve this by binding to thousands of different structures?
Dr. Jianying Yang and Prof. Dr. Michael Reth, two members of the Centre for Biological Signalling Studies BIOSS of the University of Freiburg and of the Max-Planck-Institute of Immunobiology, have now found a solution to this longstanding puzzle. Using methods of synthetic biology, namely the rebuilding of the BCR in its native and altered form, they demonstrated that on resting B lymphocytes the antigen receptors form tight oligomeric structures inhibiting the signalling of this receptor. Exposure of the cell to antigen results in the dissociation of these tight oligomers and to signalling. Interestingly, this dissociation process is independent of the ligand’s structural input and therefore explains why these receptors can be activated by thousands of structurally different ligands. The new model of BCR activation is diametrically opposed to the currently accepted model suggesting that the antigen receptors on B lymphocytes are dispersed monomers that are activated when two receptors are cross-linked by an antigen. “Our new model suggests that it is the dissociation rather than the formation of a defined BCR complex that activates B cells and this can be done by many different antigens,” explains Michael Reth.
The discovery of an ordered oligomeric structure of the antigen receptor has many implications for future research on new vaccination strategies or new treatments against B cell tumors such as leukemia or lymphomas. Indeed, dysregulated signals from the antigen receptor are associated with the development of B cell tumors. It is likely that the oligomeric antigen receptor on resting B cells is surrounded by other molecules helping it to keep silent. The search for this silencing complex is now ongoing and the two investigators are hoping that the synthetic biology tools developed by BIOSS will allow scientists to find these components of the BCR complex.