TET gene mutations in T regulatory cells unleash fatal autoimmune disease in mice

May 6, 2019

A new paper in the May 1, 2019, issue of the journal Nature Communications from the lab of La Jolla Institute for Immunology (LJI) investigator Anjana Rao, PhD, reveals that two DNA modification enzymes called TET2 and TET3 must be functional for T-regs to check auto-immunity. Those findings alone would be significant, but the paper reaches an unanticipated conclusion that could prove relevant to cancer immunotherapy.

The first conclusion was evident when the group genetically excised TET2 and TET3 only in T-regs of mice and animals died by 22 weeks of age from autoimmune disease. Mutant mice displayed bloated spleens, lymph nodes engulfed with lymphocytes and too many T effectors, the cells leading the inflammatory attack. Mutant T-regs isolated from mouse tissues had inappropriately upregulated genes associated with uncontrolled growth, DNA damage and cancer, a gene expression signature not typical of normal T-regs.

Most critically, over time mutant T-regs lost expression of the very gene that endows them with “T-reg-ness”, a master control gene called Foxp3.

There, the story took an interesting turn. Apparently as their Foxp3 expression waned, cells lacking TET2 and TET3 didn’t simply die off—as one might expect when a cell loses its identity gene. Instead, they persisted in inflamed tissues and became what immunologists call “ex-T-reg cells”. In this Jekyll-and-Hyde transition, T-regs first become unstable (in this case due to loss of TET2 and TET3) and then over time acquire the pathogenic qualities of their former foes, the T effector cells. The paper reports that some “ex-T-regs” even began secreting inflammatory cytokines that likely fomented autoimmune responses.

TET proteins are enzymes that behave functionally by removing small chemical groups called methyl groups from DNA. The removal of methyl groups can control gene activity. DNA has four bases, C, G, T amnd A, and Tet proteins modify methyl groups on C residues in adjacent CG sequences, resulting in removal of the methyl group from the C bases. Generally, highly methylated genes are silent, so demethylation by TET proteins may be required to keep them activated. Accordingly, the paper reports experiments showing that in T-reg cells lacking TET2 and TET3, genomic regions that control Foxp3 stability were hypermethylated, providing a molecular explanation for why Foxp3 became unstable.

The study demonstrates that deleting (or inhibiting) TET genes has critical consequences for T-reg cells that Xiaojing Yue, PhD, an instructor in the Rao lab and the study’s first author says, “have two sides”. On the one hand, T-regs combat autoimmunity. Thus, small molecules known to activate TET genes, among them vitamin C, may keep your immune system from mounting an inflammatory attack on your own tissues by safe-guarding T-reg stability.

But T-regs can be the foe in cancer, where immune responses to tumors are notoriously weak. Immunotherapies are successful against many cancers because they bolster anti-tumor responses by T effectors, which may require targeting T-regs.

LJI has the full article