TET proteins regulate the factors necessary for normal antibody production

Recently, the team at the La Jolla Institute of Immunology has reported in the journal Science Immunology that genetic deletion or mutation of TET2 and TET3 in mouse B cells inhibits the production of functional IgG antibodies, reducing the effectiveness of the immune response.

TET (ten-eleven translocation) protein is an α-ketoglutarate (α-KG) and Fe2+-dependent dioxygenase present in vivo, which can catalyze the conversion of 5-methylcytosine (5-mC) to 5-Hydroxymethylcytosine (5-hmC), and an important enzyme in the process of DNA demethylation, playing an important role in maintaining the pluripotency of stem cells. The TET protein is also known as a cancer suppressor protein. Mutations in the TET gene can cause a variety of tumors, especially hematopoietic tumors.

However, it is not entirely clear how the TET protein activates genes to ensure that cells function effectively in their normal function so far.

DNA can be loose or tightly hovered - tightly curling silences genes that are hidden in chromosome distortion, and gene expression proceeds as the spiral unfolds, making DNA more accessible. This process is influenced by the TET protein, which modifies the chemical structure of the DNA by altering the methyl group attached to C. C is one of the four bases A, C, T, and G of DNA. This so-called "epigenetic regulation" is the main strategy by which cells are used to turn genes on and off by altering DNA accessibility or structure.

The investigators deleted TET2 and TET3 in mature B cells at selected time points in model mice. Five days later, they took out mouse B cells and performed a series of molecular tests to compare their activity with B cells from normal mice.

A key difference is that when stimulated by experimental pathogens, mutant B cells lacking TET2 and TET3 produce an antibody called IgM, whereas normal control B cells produce a more potent IgG or "gamma globulin" antibody. Unlike IgM, IgG neutralizes pathogens, helps other cells recognize invaders (including cancer cells), and maintains the health of the organism.

The team also found that mutant cells lacking TET2 and TET3 did not produce enough protein called AID, which actually performs IgM-to-IgG splicing techniques, simply because TET2 and TET3 cannot be demethylated. Therefore, the expression of the AID gene cannot be enhanced. In mutant cells lacking TET2 and TET3, the AID gene may remain methylated, inaccessible and silent, predominating IgM antibodies.

Those who inherit the AID gene mutation (known in humans as AICDA) develop an immunodeficiency called super-IgM syndrome, in which their B cells fail to convert IgM normally into IgG antibody. These people are more susceptible to serious infections and malignant tumors.

The TET gene has not been associated with high IgM syndrome. TET2 is the most common mutated gene in blood cancers, including diffuse large B-cell lymphoma, suggesting that it can suppress cancer progression in normal B cells. More importantly, vitamin C is required for the full activity of the TET protein. The research can explain how a healthy diet enhances our immune response.

TET proteins are commonly inhibited in cancer, including cancers from the B cells mentioned. The important theoretical basis for these findings is to determine the normal function of the TET protein to better understand why cancer develops when the TET gene is inhibited.