The master regulator behind the development of antibody-producing cells has been identified in a study by investigators at Weill Cornell Medicine. The study, published in Nature Immunology, combined computational analyses with advanced molecular biology and genomic techniques to identify a protein called OCT2 as the key determinant of the B-cell humoral immune response.
"All of our cells have defense mechanisms against becoming mutated, but B cells actually do the opposite; they specialize in mutating, and they do it very fast," said co-senior author Ari Melnick. Previous studies showed that B cells control their germinal center maturation by altering the accessibility of different parts of their genomes and triggering cascades of gene expression changes to direct and limit their development.
To understand what coordinates all those signals, the researchers first took a computational approach, mapping all the gene regulation changes maturing B cells undergo. "We started off creating an atlas of all the regulatory elements that come into being and disappear over that period of time," said Melnick. By developing new computational methods, the team was able to deconvolute the changes to identify OCT2 as the molecule that appeared to be at the root of the process.
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But the distribution of OCT2 in germinal centers was surprisingly similar to its distribution in mature B-cells prior to their activation. Probing B cells with new genomic and molecular tools in the lab, the researchers found OCT2 in immature B cells pre-positioned in the genome locations where it would later operate during the germinal center reaction. Another gene regulatory protein, OCA-B, triggers the genome locations marked by OCT2 to become active, turning them into "super-enhancers" that drive the rest of the B cell maturation regulatory network. "The destiny of the cell is predetermined in a way so that if it gets the right signal, it will know how to create the germinal center B cell," concluded Melnick.