Dectin-1 epigenetic reprogramming rescues senescent-like Treg function in allergic asthma.

Tregs from allergic asthma patients exhibited a senescent phenotype with multiple markers of cellular senescence.

• Patient Tregs showed shortened telomeres compared to healthy controls.
• Increased SA-β-gal activity was observed in patient Tregs, a canonical marker of cellular senescence.
• Patient Tregs demonstrated heightened apoptosis relative to controls.
• These senescent features were accompanied by functional defects including reduced suppressive capacity.

Tregs from allergic asthma patients showed compromised function with a pro-inflammatory cytokine shift.

• Patient Tregs exhibited reduced suppressive capacity.
• A shift toward pro-inflammatory cytokine production was observed in patient Tregs.
• Functionally impaired Tregs showed reduced FOXP3 and IL-10 expression, which are core Treg signature genes.
• These functional defects are described as hallmarks of the disease.

KQS-1 treatment robustly reversed senescence-associated defects in Tregs, restoring FOXP3- and IL-10-dependent suppressive capacity.

• KQS-1 treatment restored suppressive capacity of senescent-like Tregs from asthma patients.
• Treatment rescued production of anti-inflammatory cytokines.
• Functional rescue was centered on restoration of FOXP3 and IL-10 expression.
• KQS-1 also reversed pro-inflammatory cytokine shift in patient Tregs.

KQS-1-mediated Treg rescue was dependent on Dectin-1 binding and a downstream Raf-1/ROS signaling axis.

• KQS-1 functional effects required Dectin-1 receptor binding.
• Downstream signaling proceeded through a Raf-1/ROS axis.
• CRISPR-mediated deletion of Dectin-1 abrogated all beneficial effects of KQS-1.
• The Dectin-1/Raf-1/ROS pathway drove a sustained downstream epigenetic program.

KQS-1 treatment drove a sustained epigenetic reprogramming program at FOXP3 and IL10 loci.

• Epigenetic changes included increased H3K4me3 (active transcription mark) at FOXP3 and IL10 loci.
• Increased H3K27ac (active enhancer mark) was also observed at FOXP3 and IL10 loci.
• Focal hypomethylation was detected at these specific loci.
• Chromatin remodeling occurred specifically at FOXP3 and IL10 loci.
• These epigenetic changes were described as focal and locus-specific rather than genome-wide.

KQS-1 treatment attenuated airway hyperresponsiveness, inflammation, and remodeling in a dust mite-sensitized mouse model.

• Protective effects were demonstrated in dust mite-sensitized mice.
• KQS-1 treatment reduced airway hyperresponsiveness in this model.
• Airway inflammation and remodeling were also attenuated.
• These in vivo findings served as proof-of-principle for the protective capacity of KQS-1.

Adoptive transfer of KQS-1-trained human Tregs attenuated allergic airway disease in recipient mice.

• KQS-1-trained human Tregs were transferred into recipient mice.
• Recipient mice showed attenuation of airway hyperresponsiveness, inflammation, and remodeling.
• This experiment provided additional proof-of-principle that KQS-1 functionally reprograms Tregs in a therapeutically relevant manner.
• The adoptive transfer model confirmed that KQS-1 effects are cell-intrinsic to Tregs.