Ten-eleven translocation (TET) proteins have long been known to regulate fundamental biological processes and play important roles in embryonic, neuronal, and hematopoietic development. Through their epigenetic regulation of gene expression, they have been largely implicated as cancer suppressive proteins. Now, a team at La Jolla Institute for Immunology has uncovered how the TET2 and TET3 enzymes contribute to the regulation of immunoglobulin class switching and somatic hypermutation during B-cell activation. The researchers, led by Anjana Rao, PhD, professor, division of signaling and gene expression, La Jolla Institute, reported that mutations in TET2 and TET3 in mouse B cells diminish the generation of functional IgG antibodies, decreasing the effectiveness of immune responses. The paper titled, “TET enzymes augment activation-induced deaminase (AID) expression via 5-hydroxymethylcytosine modifications at the Aicda superenhancer” is published in the journal Science Immunology. TET enzymes are dioxygenases that promote DNA demethylation by oxidizing the methyl group of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). In this study, the researchers investigated the role of TET proteins during mouse B cell activation by mapping 5hmC distribution across the genome and integrating the data with previous studies of transcriptional and epigenetic changes during B cell activation. In addition, they identify a B cell gene that becomes silenced in the absence of TET2 and TET3, highlighting how critical “epigenetic” control of gene expression is for healthy immune cell function and hinting at why TET loss promotes oncogenesis.