TET Proteins and Normal Antibody Production

A family of cancer suppressive proteins, known as TET proteins, regulates gene activity by epigenetically modifying DNA structure. However, it hasn’t been clear exactly how these TET proteins work. In a study published today in Science Immunology, researchers from La Jolla Institute report that genetic deletion or mutation of TET2 and TET3 in mouse B cells reduces the generation of functional IgG antibodies, decreasing the effectiveness of immune responses.

“Previously, people knew that TET proteins were involved in suppressing cancer,” says co–first author Chan-Wang Jerry. “But it was difficult to tease out what the normal function of TET genes was because mice developed cancer so rapidly when we deleted them.”

The new study circumvents this issue by using a conditional knock-out strategy. The researchers deleted TET2 and TET3 in mature B cells at a time point of their choice. Five days later, they removed the mouse’s B cells and performed a battery of molecular tests to compare their activity with B cells derived from normal mice. The team found that mutant B cells lacking TET2 and TET3 produced an overabundance of IgM antibodies, whereas normal B cells produced more effective IgG antibodies.

“Antibodies come in different ‘flavors,’” explains co–first author Vipul Shukla. “The standard flavor (IgM) does a poor job of activating other immune cells. So once a normal B cell encounters a pathogen, it tries to convert IgM antibodies to a more beneficial flavor to mount an effective immune response.”

Healthy B cells have no problem converting IgM to IgG using an innate gene editing trick called class switching, in which protein tools snip out IgM-specific regions in a DNA strand and paste in analogous IgG DNA sequences. However, B cells lacking TET2 and TET3 cannot perform this switch well because they don’t make enough of the splicing tool—a protein called AID—as TET2 and TET3 are essential to enhance its expression.

“TET2 is the most frequently mutated gene in blood cancers including diffuse large B cell lymphomas, which suggests that it restrains cancer progression in normal B cells,” Lio says. “More importantly, the full activity of TET proteins requires vitamin C. Our study may explain how a healthy diet may enhance our immune response.”

Image: Mutant B cells lacking TET2 and TET3 produced an overabundance of IgM antibodies, whereas normal B cells produced more effective IgG antibodies. Image courtesy of La Jolla Institute for Immunology.