Helper T-cell ‘black sheep’ may be key to precise allergy treatment

“Th9 cells are like the black sheep of helper T cells,” said lead author Daniella Schwartz, MD, an assistant professor of rheumatology at Pitt School of Medicine. “They need a perfect storm of occurrences to appear, and they are not long-lived, which makes them difficult to study. The other strange thing about Th9 cells is that they continue to function without seeing their antigen.”

T cells become activated when they encounter viruses, bacteria, or other pathogens, causing them to increase production of inflammatory proteins called cytokines, which control a suite of immune responses through the JAK-STAT signaling pathway. The main “on” switch for T cells is when the T cell receptor recognizes an antigen, a specific identifying characteristic of a threat. Beyond this specific form of activation, there is also another type of switch known as bystander activation, which does not involve the T cell receptor.

“Activation by bystanders generally requires other types of danger signals that indicate a threat,” Schwartz said. “What’s really unusual about Th9 cells is that they can be activated even without these dangerous signals.”

To learn more about how Th9 cells are activated in allergic responses, Schwartz and his team measured IL9, a cytokine produced by Th9 cells, in T cells from patients with atopic dermatitis, an allergic condition characterized by a dry, rash. with itching, and in healthy volunteers. . They found that Th9 cells from allergic patients responded to activation by bystanders, but not from healthy volunteers.

“This told us that there is some kind of checkpoint that prevents non-specific activation of Th9 cells in healthy people,” Schwartz explained. “In allergic patients, we hypothesize that the checkpoint breaks down, so the cytokine is produced even without restimulating the cells with antigen.”

In most helper T cells, when antigen binds to the T cell receptor, this highly specific recognition process causes the DNA in the T cell nucleus to unwind like thread on a spool, opening regions of DNA that encodes the production of cytokines that trigger a set of immune responses. When the threat is removed, there is no more antigen to stimulate the T cell receptors and the cells shut down. But the structure of the DNA remains open so that the cell is prepared for a possible future encounter.

Schwartz and his team found that Th9 cells have a different type of regulation. These cells are activated by transcription factors called STAT5 and STAT6, which bind to the open region of DNA around IL9 to activate the gene. Unusually, the DNA shuts down over time, stopping the production of IL9.

In healthy people, this on/off mechanism acts as a checkpoint to control immune responses that are on all the time. But when this checkpoint fails in allergy, the DNA remains open, which keeps the IL9 gene turned on and causes allergic inflammation.

In a mouse model of Th9-driven allergic asthma, blocking JAK-STAT signaling with a drug called tofacitinib, which is approved to treat rheumatoid arthritis, atopic dermatitis, and other inflammatory disorders, improved symptoms of the disease.

Analyzing data from patients with allergic asthma, the researchers found that those with higher levels of Th9 cells had greater activation of the STAT5 and STAT6-related genes. This finding supports the idea that Th9 could act as a biomarker to predict patients likely to respond to JAK inhibitors, pointing to new approaches for allergy precision medicine.

Other study authors are listed in the nature immunology paper.

This research was funded by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AI001251, ZIA-AI001202, ZIA-AI001098, ZIA-AI001240 and ZIC-AR041181). .