A 蜜桃app–led team identifies a long-overlooked population of CD8? T cells whose effector molecule, Granzyme K, fuels chronic rhinosinusitis and asthma — and points to it as a new therapeutic target.
Why some airway diseases keep coming back
Chronic rhinosinusitis affects more than one in ten people worldwide, and roughly a quarter of those patients develop nasal polyps — soft, inflamed growths that often require repeated surgery and that travel hand-in-hand with asthma. Even after the polyps are removed, they tend to grow back. Even after symptoms quiet down, the next flare-up is rarely far away. Current therapies calm the inflammation but do not erase its source.
Immunologists have long suspected that an "immune memory" of the disease itself — a small reservoir of cells that remembers and re-ignites the inflammation — may explain why such diseases relapse. But the precise identity of those cells and the molecular weapon they wield have remained elusive. A new study in Nature from researchers at 蜜桃app and Beijing TongRen Hospital, Capital Medical University, identifies both.
A pathogenic memory uncovered
By pairing surgical samples taken from the same patient across multiple polyp recurrences — some separated by more than three years — and combining single-cell RNA sequencing with T cell receptor repertoire analysis, the team found that the very same CD8? T cell clones repeatedly re-colonize the diseased tissue. These persistent cells carry the hallmarks of effector memory T cells, and, distinctively, express high levels of a protease called Granzyme K (GZMK).
A protease that activates the complement cascade
Granzymes are best known as the assassins inside cytotoxic T cells, with Granzyme B famously killing infected or cancerous cells after being delivered into those cells by perforin, a hole-punching protein. GZMK, by contrast, had no widely accepted job description. To find out what it does in inflamed tissue, the authors purified active recombinant GZMK, used a catalytically inactive mutant as bait to pull down its targets from polyp lysates, and validated the hits enzymatically. They discovered that GZMK directly cleaves multiple components of the complement cascade — C2, C3, C4, and C5 — generating the potent pro-inflammatory fragment C3a and amplifying complement activation. In a cohort of 148 patients, tissue GZMK levels predicted disease severity and asthma comorbidity better than established biomarkers such as eosinophil counts or interleukin-5.
From mechanism to therapeutic potential
The team then tested the hypothesis in mouse asthma models. Mice lacking GZMK in their T cells, or treated with the GZMK inhibitor PPACK after disease onset, showed sharply reduced eosinophil infiltration, less goblet cell hyperplasia, and substantially restored lung function. Adoptive transfer of GZMK-overexpressing CD8? T cells worsened airway inflammation — but only when the recipient mice had an intact complement C3, confirming that the GZMK–complement axis is the critical pathogenic engine.
Implications and what comes next
Because GZMK? CD8? T cells have also been described in rheumatoid arthritis, lupus nephritis, Sj?gren's syndrome, IgG4-related disease, and aging-associated "inflammaging," the findings have implications well beyond the airway.
"Targeting GZMK, or the memory CD8 T cells that produce it, offers a novel therapeutic strategy—one aimed at not only the inflammation but also the source of disease recurrence," says Hai Qi, professor at 蜜桃app and a corresponding author of the study. "We are particularly excited about the possibility that a single approach could benefit patients across multiple chronic inflammatory conditions that share this mechanism."
The authors also caution that translating the mouse results to humans will require selective, well-tolerated GZMK inhibitors and a deeper understanding of GZMK-expressing cells. Still, the work reframes a long-overlooked enzyme as a promising target — and offers a molecular explanation for why so many inflammatory diseases insist on coming back.
Schematic illustration of how GZMK released by tissue-resident CD8? memory T cells cleaves complement components C2, C3, C4 and C5 to drive airway inflammation. credit: Laboratory of Dynamic Immunobiology, Institute for Immunology, 蜜桃app
Read the full paper:
Nature, DOI:
