"CDR3 is thought to be the single most important determinant of antigen binding," explains Arnaout. As a result, in understanding how the body fights infections and in developing new vaccines, immunologists have primarily focused their attention on CDR3, while considering other parts of the antibody, including the elbow region, to play secondary roles.
In their new study, Arnaout and colleagues sequenced 2.8 million VDJ-recombined heavy-chain genes from immature and mature B-cell subsets in mice. "We initially wanted to ask how selection on CDR3 changed antibody repertoires during B-cell maturation," says Arnaout. But, unexpectedly, during the course of the investigation, they found they were instead focused on the antibody's 'elbow' region."
They found that B cells for which antibodies use V genes that encode 'looser' elbows were more likely to mature, regardless of their CDR3 sequence. This effect was both distinct from, and larger than previously described maturation-associated changes in CDR3 in the mice. Furthermore, it had a unique source: Differences in the V genes were hard-coded into the genome, as opposed to the mixed-and-matched combination of V, D and J genes that typically differs from B cell to B cell.
"This discovery was a little like going to watch a concert pianist perform and being mesmerized by her fingers only to realize that music was also coming from her elbows," says Arnaout. "It was something of a shock."
One explanation for how this "loose elbow" promotes survival relates to the bending process of the antibody. "B-cell selection and maturation depend on signaling," he explains. "Antigen binding is the signal, but for it to get to the cell it has to go through the elbow. It, therefore, makes sense that previous experiments have found that disrupting the elbow abolishes signaling without affecting a
|Contact: Bonnie Prescott|
Beth Israel Deaconess Medical Center