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Clues to how B cells establish affinity

Spread-and-contract mechanism allows B lymphocytes to gather high-affinity antigens

By | May 5, 2006

In the early moments of an immune response, B lymphocytes spread around cell membranes containing foreign antigens and gather these antigens into aggregates, according to a paper in this week's Science. The authors also found that B cells spread farther around membranes containing high-affinity antigen, which leads to increased antigen accumulation and B cell activation. "This could be a mechanism that would allow for affinity maturation," in which B cells that produce antibodies with high antigen affinity are selected for survival by the immune system, said Anthony DeFranco of the University of California, San Francisco, who was not involved in the study. Previous work by senior author Facundo Batista of the Cancer Research UK London Research Institute and his colleagues revealed that when a B cell recognizes an antigen embedded in a cell membrane, an immunological "synapse" -- composed of clusters of B cell receptors, antigens, and adhesion molecules -- forms between the two cells, and the B cell acquires the antigen for processing and presentation to T cells. But how B cells discriminate between low- and high-affinity antigens remained unclear, Batista said. Led by Sebastian Fleire, also of London Research Institute, the researchers used scanning electron microscopy to watch cells containing surface lysozyme molecules interact with transgenic B cells carrying a receptor specific for this lysozyme. By labeling the antigen molecules with GFP, the researchers could watch as the B cells rapidly spread over the cell membranes, collecting lysozyme antigen, and then slowly contracted again, gathering the ligands into a central cluster. By using a panel of mutant lysozymes with various affinities for the B cell receptor, the researchers next showed that the affinity between the receptor and antigen correlated directly with the degree of B cell spreading. To help explain this correlation, they created a mathematical model based on their experimental measurements of receptor-antigen interactions. The model revealed that high-affinity antigens occupy many B cell receptors, leading to cell attachment and B cell spreading. This spreading exposes more B cell receptors, which can then bind even more ligand and continue the process. Low-affinity ligands, on the other hand, occupy too few B cell receptors to perpetuate contact and spreading between the two cells. The amount of B cell spreading determines the amount of antigen collected, and therefore establishes the ability of B cells to present antigen-derived peptides to T cells, Batista said. In this way, the immune system could distinguish which B cells have the most affinity for a particular antigen, he added. "Figuring out how it's going to apply to real immune responses is still a bit of a conjecture," DeFranco told The Scientist. While it's possible that this mechanism could be used by B cells mounting a primary immune response against antigen embedded in a bacterial cell or virion, this response generally requires only low-affinity interactions, DeFranco said. The ability to discriminate between high- and low-affinity interactions would be more useful when cells in the lymph nodes display previously encountered antigen. In that case, B cells with "the higher affinity would take up more of the antigen and be able to present it to the T cell," DeFranco said. "That's exactly where this phenomenon would come into play most effectively." Batista and his colleagues also used their mathematical model to make a prediction about the B cell system. If they inactivated the spreading mechanism in the model -- so that cells simply contacted each other at a fixed spot -- they found that the amount of antigen accumulated by the B cell was similar for both low- and high-affinity antigens. When they then performed experiments using transgenic B cells with defective spreading, they found the same result. Validating the model with an experimental prediction makes their model more convincing than those that simply describe biological observations, said Ronald Germain of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., who was not involved in the study. "For B cells, this is a pretty new way of thinking, and it is very new to combine modeling to try to really work out mathematically how this works." Melissa Lee Phillips mphillips@the-scientist.com Links within this article S.J. Fleire et al., "B cell ligand discrimination through a spreading and contraction response," Science, May 5, 2006. http://www.sciencemag.org T. Toma, "Early determination of B cell fate," The Scientist, May 22, 2002. http://www.the-scientist.com/article/display/20403/ J.U. Adams, "Promoting antibody diversity, The Scientist, December 5, 2005. http://www.the-scientist.com/article/display/15899/ Anthony DeFranco http://www.ucsf.edu/immuno/faculty/DeFranco_main.htm Batista et al., "B cells acquire antigen from target cells after synapse formation," Nature, May 24, 2001. PM_ID: 11373683 Facundo Batista http://science.cancerresearchuk.org/research/loc/london/lifch/batistaf/ J.P. Roberts, "Dissecting the immunological synapse," The Scientist, May 5, 2003. http://www.the-scientist.com/2003/05/05/28/1/ M.M. Davis, "Panning for T-cell gold," The Scientist, July 19, 2004. http://www.the-scientist.com/article/display/14833/ L. Harris, "SEM goes live," The Scientist, March 15, 2004. http://www.the-scientist.com/article/display/14522/ Ronald Germain http://www.niaid.nih.gov/dir/labs/li/germain.htm
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