FCGR3A+CD8+ cytotoxic T effector subset with NK-cell-like features promotes disease progression in eosinophilic chronic rhinosinusitis with nasal polyps

Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) and non-eosinophilic chronic rhinosinusitis with nasal polyps (neCRSwNP) have distinct immune-dysregulation profile and clinical features. Gaining insight into their pathogenic mechanisms could help distinguish them and facilitate their diagnosis and treatment. Therefore, we first evaluated the transcriptional profiles of 68,273 nasal polyp cells from patients with eCRSwNP or neCRSwNP using a existing single-cell sequencing database. Eight major cell types were categorized into 50 immune-cell subsets. Gene Ontology analyses of differentially upregulated genes was performed for all 50 subsets in both groups to identify enriched pathways and transcription factors with different activities. A database of known receptor–ligand pairs was used to assess intercellular communications. Potential interaction strengths were predicted based on the expression of the ligand–receptor pairs. We mined CRS risk-gene expression levels in each immunocyte subset based on previous data. Using our patient cohort, we validated the bioinformatics findings and demonstrated their correlation with disease severity. Flow cytometry was used to verify and detect the abundances of type-2 innate lymphoid cells, effector T (Teff) cells, natural killer cells (NKs), and FCGR3A+CD8+ Teff cells in our patients with CRSwNP. Besides, immunofluorescence staining and clinical correlation analysis of FCGR3A+CD8+ Teff cells were also performed. Compared to neCRSwNP patients, those with eCRSwNP showed significantly increased proportions of CD8+ Teff and CD56dimCD16+ NK cells, both exhibiting enhanced cytotoxic activity. FCGR3A+CD8+ Teff cells were significantly increased in eCRSwNP versus neCRSwNP patients, with their expansion correlating with both enhanced cytotoxic activity and worse clinical severity. FCGR3A+CD8+ Teff cells exhibited enhanced cytotoxic profiles in terms of gene expression, pathway enrichment, and intercellular communication. Compared to FCGR3A-CD8+ Teff cells that upregulated GZMK, FCGR3A+CD8+ Teff cells upregulated GZMB. Patients with eCRSwNP also showed significantly activation of tissue-remodeling responses and broadly upregulated expression of CRS-risk genes. In summary, We identified an NK-like cytotoxic FCGR3A+CD8+ Teff subset involved in eCRSwNP disease progression that correlated with CRSwNP disease severity. Our findings showed that patients with eCRSwNP and neCRSwNP exhibited extensive cellular heterogeneity, i.e. the sinus tissues of patients with eCRSwNP showed a highly cytotoxic immune microenvironment than those of patients with neCRSwNP. Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License.

Authors Metrics & Citations Metrics Article Usage 288views 138downloads Citations Download citation Zhichen Liu, Chunxi Ke, Ning Lu, et al. FCGR3A+CD8+ cytotoxic T effector subset with NK-cell-like features promotes disease progression in eosinophilic chronic rhinosinusitis with nasal polyps. Authorea. 09 June 2025. DOI: https://doi.org/10.22541/au.174947427.79294305/v1 DOI: https://doi.org/10.22541/au.174947427.79294305/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.