A research collaboration between the Henan Academy of Innovations in Medical Science, Zhengzhou University, and Shenzhen University School of Medicine has identified a mechanism of regulatory T cell (Treg) dysfunction in allergic asthma and showed how to their activity. The study, published in Life Science Alliance, shows that Tregs in patients with allergic asthma enter a senescence-like, functionally impaired state, and that engaging the Dectin-1 receptor can reverse this defect improving anti-inflammatory function in both human cell lines and mouse models.
“This raises the intriguing possibility of harnessing such pathways to durably ‘re-educate’ and restore core functional pathways of dysfunctional immune cells like Tregs,” said co-senior author Pingchang Yang, MD, PhD, a professor of immunology at Shenzen University School of Medicine.
Allergic asthma is characterized by immune dysregulation partially driven by an imbalance in pro-inflammatory and anti-inflammatory Tregs. Tregs are defined by expression of the transcription factor FOXP3 and their ability to suppress inflammation through cytokines such as IL-10. Previous research the both the number of Tregs, and their function, are reduced in asthma and are connected to disease severity. While this correlation is known, the mechanisms behind immune impairment has not been characterized. Other evidence has suggested that chronic inflammation, such as that seen in asthma, can induce a senescence-like state in Tregs that alters their function metabolism.
To see if it is possible to reverse this state in Tregs, the investigators isolated Tregs from allergic asthma patients and discovered the showed signs of this senescence-like state. This state was marked by shortened telomeres, increased senescence-associated β-galactosidase activity, and increased apoptosis. Additionally, these Tregs showed a shift toward pro-inflammatory cytokine production.
The team focused on the Dectin-1 receptor on Tregs. This is a C-type lectin receptor known for recognizing fungal β-glucans and mediating innate immune responses. Recent studies have indicated that Dectin-1 may also influence adaptive immunity, including T-cell function. Tregs express Dectin-1, and its activation can trigger intracellular signaling pathways that influence gene expression. The researchers hypothesized that targeting Dectin-1 could reverse Treg dysfunction by reprogramming key regulatory genes.
To test this, they used a fungal polysaccharide-derived peptide, KQS-1, which binds Dectin-1 with high affinity. In vitro experiments showed that KQS-1 treatment restored FOXP3 and IL-10 expression in patient-derived Tregs. This was linked to epigenetic changes including increased activating histone marks, reduced DNA methylation, and chromatin remodeling. These changes were driven by a Dectin-1–dependent signaling pathway involving Raf-1 and reactive oxygen species (ROS). “This functional rescue centered on these two core Treg signature genes was dependent on Dectin-1 binding and a downstream Raf-1/ROS signaling axis,” the researchers wrote. The team also found that CRISPR-mediated deletion of Dectin-1 eliminated the beneficial effects of KQS-1, which demonstrated that the receptor is required for this process.
Building on this information, the team then tested human Tregs treated with KQS-1 in mouse models and showed that it reduced airway hyperresponsiveness, inflammation, and tissue remodeling. Based on this, the researchers concluded that Treg dysfunction in asthma involves a reversible, senescence-like state centered on loss of FOXP3 and IL-10 activity. “This study identifies the acquisition of a senescence-like and dysfunctional phenotype in Tregs as a pivotal mechanism in the pathogenesis of allergic asthma and unveils a novel therapeutic strategy to reverse this defect,” they wrote.
The could potentially lead to new therapeutic strategies that reprogram immune cells, as opposed to current approaches that broadly suppress inflammation. By targeting Dectin-1, it could be possible to selectively restore Treg function and improve immune regulation in asthma and other immune-mediated diseases.
The research team will now study the safety, dosing, and pharmacokinetics of KQS-1. They will also look to discover if its effects extend beyond FOXP3 and IL10 to broader Treg lineage stability.
