Immune brakes turn into attackers in autoimmune disease

Regulatory T cells, or Tregs, act as a counterweight in the immune system. They suppress other immune cells when those become overactive. Normally, Tregs are stable, even though they recognize the body’s own proteins with relatively high sensitivity. Two proteins, DGK-alpha and DGK-zeta (diacylglycerol kinases), play a key role in maintaining that stability.

In the study, published in eLife, mice were created in which only the Tregs lacked both DGK proteins. The outcome was striking. The Tregs lost their stability, switched to an attacking mode, and caused autoimmune disease in multiple organs. They transformed specifically into a cell type that excessively activates germinal center B cells in lymph nodes, leading to the production of self-targeting antibodies.

What this tells us about aging

During normal aging, Tregs gradually become less stable. The immune system becomes less well regulated, which contributes to chronic low-grade inflammation. This mechanism, in which suppressive cells convert to a harmful form, is a possible explanation for why autoimmune-like features become more common at older ages.

The DGK proteins are therefore interesting as potential targets. If their activity declines with aging, that could help explain why the Treg brake works less effectively in older people. That remains a hypothesis, not demonstrated by this study.

Implications for treatment

For autoimmune disease, this research opens a new angle: rather than broadly suppressing the immune system, selectively restoring DGK function in Tregs could offer a more precise approach. That is still far from clinical application. But the finding that a single signaling molecule plays such a large role in preventing self-immunity provides a useful target for follow-up research.

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