Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1.
T cell polyfunctionality is a hallmark of protective immunity against pathogens and cancer, yet the molecular mechanism governing it remains mostly elusive. We found that canonical Wnt agonists inhibited human memory CD8+ T cell differentiation while simultaneously promoting the generation of highly polyfunctional cells. Downstream effects of Wnt activation persisted after removal of the drug, and T cells remained polyfunctional following subsequent cell division, indicating the effect is epigenetically regulated. Wnt activation induced a gene expression pattern that is enriched with stem cell-specific gene signatures and upregulation of protein arginine methyltransferase 1 (PRMT1), a known epigenetic regulator. PRMT1+CD8+ T cells are associated with enhanced polyfunctionality, especially the ability to produce IL-2. In contrast, inhibition of PRMT1 ameliorated the effects of Wnt on polyfunctionality. Chromatin immunoprecipitation revealed that H4R3me2a, a permissive transcription marker mediated by PRMT1, increased at the IL-2 promoter loci following Wnt activation. In vivo, Wnt-treated T cells exhibited superior polyfunctionality and persistence. When applied to cytomegalovirus (CMV) donor-seropositive, recipient-seronegative patients (D+/R-) lung transplant patient samples, Wnt activation enhanced CMV-specific T cell polyfunctionality, which is important in controlling CMV diseases. These findings reveal a molecular mechanism governing T cell polyfunctionality and identify PRMT1 as a potential target for T cell immunotherapy.
Duke Scholars
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Related Subject Headings
- Wnt Signaling Pathway
- Wnt Proteins
- Repressor Proteins
- Protein-Arginine N-Methyltransferases
- Memory T Cells
- Lung Transplantation
- Interleukin-2
- Immunology
- Humans
- Epigenesis, Genetic
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Location
Related Subject Headings
- Wnt Signaling Pathway
- Wnt Proteins
- Repressor Proteins
- Protein-Arginine N-Methyltransferases
- Memory T Cells
- Lung Transplantation
- Interleukin-2
- Immunology
- Humans
- Epigenesis, Genetic