Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1

Bo Yi Sung, Yi Hsin Lin, Qiongman Kong, Pali D. Shah, Joan Glick Bieler, Scott Palmer, Kent J. Weinhold, Hong Ru Chang, Hailiang Huang, Robin K. Avery, Jonathan Schneck, Yen Ling Chiu

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number140508
JournalJournal of Clinical Investigation
Issue number2
StatePublished - Jan 18 2022

ASJC Scopus subject areas

  • Medicine(all)


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