Rare helper T cell linked to allergic disease: New precision medicine approaches in treating allergies

Researchers from the University of Pittsburgh and the National Institutes of Health have conducted a study published in Nature Immunology that sheds light on the mechanisms behind how Th9 can trigger allergic reactions. Th9 cells are a rare type of helper T cell that requires specific circumstances to become active and are difficult to study due to their short lifespan. Unlike other T cells, Th9 cells can remain active without encountering their target antigen. When T cells are activated, they produce cytokines that trigger immune responses.

The activation of T cells is usually triggered by the T cell receptor recognizing an antigen. However, bystander activation can also occur in the absence of the T cell receptor. Th9 cells can be activated by bystander activation even without the presence of dangerous signals, which is unique. The researchers measured the cytokine IL9 in T cells from patients with atopic dermatitis and healthy volunteers to understand how Th9 cells are activated during allergic responses. They found that Th9 cells from allergy patients were activated through bystander activation, whereas Th9 cells from healthy volunteers were not.

The researchers hypothesized that a checkpoint in healthy individuals prevents the non-specific activation of Th9 cells. When the checkpoint fails in allergy patients, cytokine production occurs without restimulation with antigen. When antigen binds to the T cell receptor of most helper T cells, specific recognition occurs, which causes DNA in the nucleus to unwind and open regions of DNA that encode the production of cytokines that initiate immune responses. When the threat is eliminated, the T cells turn off, but the DNA structure remains open for possible future encounters.

Schwartz and her team discovered that Th9 cells have a unique mode of regulation that involves STAT5 and STAT6 transcription factors binding to open regions of DNA around the IL9 gene to activate it. Unlike other T cells, the DNA around IL9 closes over time, stopping the production of cytokines, and acting as a checkpoint to prevent the immune response from being continuously activated. However, in allergic individuals, this checkpoint mechanism breaks down, and the DNA remains open, causing IL9 gene expression to continue and driving allergic inflammation.

The researchers tested the effects of tofacitinib, a drug used to treat rheumatoid arthritis, atopic dermatitis, and other inflammatory conditions, on a mouse model of allergic asthma driven by Th9 cells. Blocking JAK-STAT signaling with tofacitinib improved disease symptoms, indicating the potential of JAK inhibitors as a treatment for allergic diseases.

The team analyzed data from patients with allergic asthma and found that those with higher levels of Th9 cells had increased activation of STAT5 and STAT6-related genes. This discovery suggests that Th9 cells could serve as a biomarker to predict patients who are likely to respond to JAK inhibitors, providing new possibilities for precision medicine in allergy treatment.

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