New study reveals how unstable immune cells drive chronic liver disease and points to a promising dual therapy

Primary sclerosing cholangitis (PSC) is a chronic liver disease that damages the bile ducts and currently has no effective cure. The exact cause of PSC is unknown, although recent studies have indicated that PSC is driven by the immune system. Patients with PSC show a reduction and impaired function in regulatory T cells (Tregs) - immune cells that normally calm inflammation and help tissues repair themselves. 

IRR Group Leader Dr Wei-Yu Lu and colleagues at the University of Birmingham and in Japan explored why Treg numbers and function are impaired in PSC and the effect this has. 

Fewer regulatory T cells make it harder for bile ducts to repair

In this study, researchers used clinical data and laboratory models that imitate PSC bile duct injury and reduce Treg levels. They found that when Treg numbers are reduced around the bile ducts, the liver’s natural repair response becomes weaker. As a result, fewer new bile duct cells are produced, and liver scarring (fibrosis) increases. 

The Ox40L molecule makes regulatory T cells unstable and less able to control the immune response

The team then examined what happens to Tregs during bile duct injury. They discovered that many liver Tregs became unstable and transform into pro-inflammatory “exTregs.” These exTregs produce inflammatory molecules and may worsen bile duct damage. Importantly, even when Treg numbers were manually increased - using a method called IL-2 therapy - many still turned into dysfunctional exTregs, revealing a major obstacle for PSC treatment.

The researchers identified a key driver of this instability: Ox40L, a molecule expressed in the liver and involved in immune activation. Ox40L was found to be elevated in PSC patients and closely associated with areas of fibrosis. 

Boosting Treg numbers and stability with IL-2 therapy and blocking Ox40L promotes tissue regeneration

Blocking Ox40L in laboratory models reduced inflammation, decreased liver scarring, and prevented Tregs from becoming exTregs. However, Ox40L blockade alone was not enough to fully restore bile duct regeneration. The most promising results came from a combined approach. When IL-2 therapy (to increase Treg numbers) was paired with Ox40L blockade (to keep Tregs stable), the treatment led to:

• more healthy, functional Tregs
• fewer harmful exTregs
• reduced liver fibrosis
• improved bile duct regeneration

This dual strategy outperformed either treatment alone, although it did not completely eliminate disease features. The study further suggests that combining additional immune-targeting approaches may help prevent Tregs from developing inflammatory traits altogether.

Overall, the findings highlight that the main challenge in PSC is not just low Treg numbers, but unstable Tregs that can switch into damaging, inflammatory cells. Successful treatments may therefore need to both increase Treg numbers and protect them from losing their stability. Targeting molecules like Ox40L may significantly enhance the effectiveness of future Treg-based therapies for PSC.