STAT5, STAT6 activate Th9 cells to promote allergic inflammation

Important points:

• STAT5 and STAT6 transcription factors activate Th9 cells.
• Th9 cells produce the IL-9 cytokine that triggers allergic inflammation.
• Th9 levels may indicate which patients respond to JAK inhibitors.

According to a study published in , Th9 can cause allergic diseases and may be a target for precision medicine to treat patients with high levels of this helper T cell. Innate Immunology.

Upon encountering viruses, bacteria, and other pathogens, T cells are activated and produce increased cytokine production. Daniela M. Schwartz, medical doctor, Written by an assistant professor of rheumatology at the University of Pittsburgh School of Medicine and a colleague.

As pro-inflammatory proteins, cytokines control a range of immune responses through the JAK-STAT signaling pathway, researchers continued. in particular, T cells become activated when their receptors recognize antigens.

However, T cells are also activated by bystander activation, but this does not involve receptors. Instead, bystander activation occurs when other kinds of danger signals indicate threat, the researchers write.

Furthermore, Th9 cells do not need to activate these dangerous signals to see the antigen continue to function. But they need a “perfect storm” to emerge, and they don’t live very long, researchers say.

Schwartz says this “frustrating” instability is one of the reasons researchers chose to study Th9 cells.

“They are so short-lived that mouse models of airway inflammation require entering the lab at 9 p.m. at night before they can be analyzed to treat them with inflammatory stimuli,” Schwartz said. told Healio. “Earlier than that, the cells would start to lose their phenotype.”

Daniela M. Schwartz

Many researchers have noticed this highly unusual behavior, but no one knows how or why it happens, Schwartz said. I kept thinking there must be an academic reason.

“When we were culturing Th9 cells in vitro, we noticed that the cultures were frantically pumping out the inflammatory mediator IL-9, even if they were just resting quietly,” she says. said. “So we thought this was probably an Occam’s razor case: her one related mechanism that explains two unique behaviors.”

Study design and results

Calling Th9 the “black sheep of helper T cells,” researchers measured IL-9, a cytokine produced by Th9 cells, in healthy patients and patients. Patients with atopic dermatitisTh9 cells from AD patients responded to bystander activation, whereas cells from healthy volunteers did not.

These results suggest that some kind of checkpoint prevents nonspecific activation of Th9 cells in healthy people, the researchers wrote. Researchers hypothesized that in allergic patients, this checkpoint is disrupted, allowing the cells to produce cytokines without being restimulated with antigen.

When an antigen binds to the T-cell receptor on most helper T-cells, the DNA in the T-cell nucleus unwinds, opening up regions of DNA that code for cytokine production and unleashing a multitude of immune responses, the study found. person writes.

When the threat is eliminated and there is no antigen to stimulate the T-cell receptors, the cells become inactive, researchers say. However, the DNA structure remains open, allowing the cell to prepare for potential future encounters.

The researchers said it is regulated differently in Th9 cells. Transcription factors called STAT5 and STAT6 bind to open regions of DNA around IL-9 to activate genes and activate cells. Unusually, the researchers say, DNA shuts down over time and IL-9 production stops.

This opening and closing mechanism serves as a checkpoint for managing immune responses in healthy individuals. However, in allergic individuals, disruption of this checkpoint leaves the DNA open, leaving the IL-9 gene activated and triggering allergic inflammation.

Blocking JAK-STAT signaling with tofacitinib (Xeljanz, Pfizer), which treats rheumatoid arthritis, Alzheimer’s disease, and other inflammatory diseases, reduced disease symptoms in a mouse model of Th9-driven allergic asthma. Improved.

Analysis of data from patients with asthma revealed that STAT5- and STAT6-related genes were more activated in patients with higher levels of Th9 cells, suggesting that Th9 responds to JAK inhibitors and has a role in the following diseases: was shown to be a possible biomarker for predicting patients who are likely to develop A New Approach to Precision Medicine in Allergy Treatment.

Impact on treatment

Schwartz argued that STAT-dependent T cells are usually seen as responding to specific antigens or pathogens or danger signals, including Th2 cells, which Schwartz described as the classical T helper subset associated with allergic disease. He said the bystander activation was amazing.

“However, STAT5/6-activating cytokines are not really red flags. They are not only found in the context of immune responses, but also during development, during wound healing, or under homeostatic conditions.” If your cells are poised to respond to these cytokines, you can imagine that would be quite undesirable.”

This allowed researchers to understand why Th9 cells do not stay around longer during inflammatory responses.

“We were also surprised that healthy volunteer T cells did not respond to these STAT-activating cytokines, but T cells from allergic patients did,” Schwartz said. “That’s why we really ask whether this ‘negative checkpoint’ of systemic instability can be disrupted in allergies, and whether it can affect patient selection/treatment.” That’s the reason.

Based on these findings, Schwartz said Th9 cells could be both targets and biomarkers of allergy. If Th9 cells are primed to respond quickly to his STAT-activating cytokines, blocking that activation loop may prevent relapses of allergic disease, he said. said.

“Because of the importance of STAT-dependent signaling for acute Th9 activation, the presence of Th9 cells in the lung or circulation may be a biomarker suggesting that JAK inhibitors are effective in allergic patients. I suggest,” she said.

JAK-STAT signaling is important for many different cytokines, Schwartz noted, adding he didn’t want to suggest that JAK inhibitors wouldn’t block other pathways.

“However, in our analysis, patients with high Th9 cells also had upregulated JAK-STAT signaling pathways in blood and tissue and responded well to JAK-SYK inhibitors in previously published clinical trials. I did,” she said.

Investigators are next interested in prospectively determining whether Th9 and IL-9 predict response to JAK inhibition in allergic disease.

“Following these mechanisms to understand how IL-9 genetic variants contribute to the pathogenesis of inflammatory diseases and how it interacts with this bystander activation pathway. We are also very interested in it,” Schwartz said.

“Finally, we would like to understand why Th9 cell lineage instability is disrupted in allergy and whether there are ways to reduce the stability of allergic Th9 cells back to a healthy/suppressed state. ‘ she said.