How Thymic stromal lymphopoietin (TSLP) Helps and Hinders Allergies

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A new study in the journal ScienceImmunology looks at a special protein called TSLP and how it affects allergies. TSLP is known to be involved in allergic reactions, but this study shows it has a more complex job. It turns out TSLP doesn't just make allergies worse; it also helps to control them. It does this by working on special cells called regulatory T cells (Tregs), which are like the peacekeepers of our immune system. The research shows that TSLP works in a clever way to both cause and then limit allergic reactions.

What the scientists found

• TSLP and Tregs: The scientists discovered that Tregs have a lot of the 'landing sites' (receptors) for TSLP on their surface. This means Tregs are very good at grabbing onto TSLP. When they do, it helps the Tregs to do their job of calming down the immune system. These 'landing sites' increase when Tregs are activated and during allergic reactions. Human Tregs also have more of these 'landing sites' than other types of immune cells.

• TSLP makes Tregs stronger: When Tregs are exposed to TSLP, it boosts certain genes that help the Tregs stay strong and stable. These genes are like instructions that tell the Tregs how to do their job properly.

• What happens when TSLP can't reach T Cells? When scientists stopped TSLP from reaching all immune cells (T cells), there were fewer of the cells that cause allergies (TH2 cells), and less lung inflammation. This shows TSLP does help to create allergic reactions. But the mice also had fewer Tregs, which suggests TSLP also helps Tregs.

• What happens when TSLP can't reach just Tregs? When the scientists blocked TSLP from reaching only Tregs, the allergic reaction got worse. This meant there were more of the cells that cause allergies and more inflammation. This is because TSLP is important for Tregs to do their job of controlling allergic reactions.

• Tregs losing control: When TSLP couldn't reach Tregs, these Tregs lost their ability to calm down the immune system. Instead, they started acting like the cells that cause allergies. They started making more of the substances that cause allergic reactions.

• Tregs turning into allergy cells: Scientists discovered that when TSLP can’t reach Tregs, the Tregs started turning into cells that cause allergies. They switched on genes that make allergy cells and switched off genes that make Tregs suppress the immune system. They also stopped making a substance called granzyme B, which helps Tregs to suppress other cells.

• TSLP can calm things down: In normal mice, if they were given TSLP before an allergic trigger, it reduced lung inflammation. However, this didn't happen when Tregs couldn't receive the TSLP signal. This proves that the calming effect of TSLP needs Tregs to function properly.

What this means
These findings show that TSLP has two jobs in allergies. On one hand, it helps the cells that cause allergies to become active and cause inflammation. On the other hand, it helps the Tregs to calm down the immune system and stop allergic reactions from getting out of hand.
The study also found that when Tregs can't receive TSLP, they can't suppress type 2 inflammation. But these Tregs were still able to suppress immune responses in other situations, like in a lab dish or in another type of inflammation in mice. This suggests that the loss of Treg function due to TSLP deficiency is only for type 2 allergic responses.

Why this is important
This research is important for understanding and treating allergies. Doctors are already using a medicine that blocks TSLP to treat asthma. This medicine works by stopping TSLP from activating the cells that cause allergies. But this research suggests that it might also affect how TSLP works on Tregs, and this might not always be a good thing.

The scientists say that more research is needed to fully understand how TSLP works in the human body. This study adds more information to our understanding of TSLP and how it works. This could lead to new treatments that target TSLP's effect on both the cells that cause allergies and the Tregs that control them. It also shows how delicate the balance in the immune system is.

This research gives us useful insights into how allergies work and points to new ways of treating them by looking at how TSLP affects both the cells that cause allergies and the cells that control them.
 
Additional information: TSLP acts on regulatory T cells to maintain their identity and limit allergic inflammation. Science Immunology (2025). 10.1126/sciimmunol.adk0073
Journal information: https://www.science.org/journal/sciimmunol