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...

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Published in:The Journal of clinical investigation 2022-01, Vol.132 (2)
Main Authors: Sung, Bo-Yi, Lin, Yi-Hsin, Kong, Qiongman, Shah, Pali D, Glick Bieler, Joan, Palmer, Scott, Weinhold, Kent J, Chang, Hong-Ru, Huang, Hailiang, Avery, Robin K, Schneck, Jonathan, Chiu, Yen-Ling
Format: Article
Language:English
Subjects:
Care and treatment
CD8 lymphocytes
CD8-Positive T-Lymphocytes - immunology
Cell differentiation
Cytomegalovirus infections
Development and progression
Epigenesis, Genetic - immunology
Epigenetic inheritance
Gene expression
Genetic aspects
Health aspects
Humans
Immunological research
Immunology
Interleukin-2 - immunology
Lung Transplantation
Memory T Cells - immunology
Protein-Arginine N-Methyltransferases - immunology
Repressor Proteins - immunology
Wnt proteins
Wnt Proteins - immunology
Wnt Signaling Pathway - immunology
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Summary: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI140508