Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 2, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI140508
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Categories
Funding
- NIH [R01-CA108835, R21-EB023411, R33-CA229042, P41-EB028239]
- Clinical Trials in Organ Transplantation [CTOT U01AI113315-1]
- National Defense Medical Research [MAB-108-086]
- Tri-Service General Hospital [TGSH-E-109229]
- Ministry of Science and Technology [MOST 106-2314-B-418-008-MY3]
- Far Eastern Memorial Hospital [103-FTN01]
- Wojcicki-Troper foundation
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This study reveals a molecular mechanism governing T cell polyfunctionality, involving the activation of Wnt signaling and the role of PRMT1. Wnt activation inhibits T cell differentiation and promotes the generation of highly polyfunctional cells, with persistent effects even after the removal of the drug. PRMT1 is involved in regulating T cell polyfunctionality, particularly the production of IL-2. These findings highlight PRMT1 as a potential target for T cell immunotherapy.
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.
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