Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1
Bo-Yi Sung, … , Jonathan Schneck, Yen-Ling Chiu
Bo-Yi Sung, … , Jonathan Schneck, Yen-Ling Chiu
Published January 18, 2022
Citation Information: J Clin Invest. 2022;132(2):e140508. https://doi.org/10.1172/JCI140508.
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Research Article Immunology

Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1

Abstract

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.

Authors

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

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Figure 5

PRMT1 highly correlates with CD8+ T cell polyfunctionality.

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PRMT1 highly correlates with CD8+ T cell polyfunctionality. (A) Intracel...
(A) Intracellular staining for cytokines and PRMT1 expression in memory CD8+ T cells in different treatment conditions. PRMT1 staining is illustrated on the x axes versus cytokine production (y axes). Black and red numbers represent percentages of cytokine-positive cells and PRMT1 MFI, respectively. (B) Pie charts showing the polyfunctionality profile of the different treatment conditions. Bar graphs display PRMT1 MFI of T cell subsets of different degrees of polyfunctionality of each treatment condition (n = 4). 0, 1, 2, 3 are defined as the number of positive cytokines. (C) PRMT1 MFI in IL-2+, IFN-γ+, or TNF-α+ CD8+ cells undergoing 7 days of CD3/CD28 stimulation from multiple healthy donors (n = 10). Mann-Whitney U test. (D) Combined PRMT1 protein and RNA detection with polyfunctionality profile by flow cytometry. Green and red boxes represent top and bottom 30% of PRMT1-expressing cells, respectively. Black lines in the plots indicate the MFI of PRMT1 protein and RNA in control group. Pie charts show the polyfunctionality profile of PRMT1hi/lo (green/red) cells in the presence or absence of SKL2001. (E) MFI of PRMT1 protein and mRNA were plotted by different polyfunctionality combinations. Squares and circles represent PRMT1 protein and mRNA levels, respectively. (F) Percentages of IFN-γ+ (black), TNF-α+ (blue), and IL-2+ (red) of all CD8+ cells in PRMT1 hi versus lo cells (filled or grid) following treatment with DMSO or SKL2001 (n = 3). Mann-Whitney U test. (G) Memory CD8+ cells treated with DMSO or SKL2001 were stratified into approximately 20–30 tiers according to MFI of PRMT1. Each tier contained at least 500 cells, and polyfunctionality was computed from individual tiers before being plotted against PRMT1 MFI in linear regression analysis.*P < 0.05; **P < 0.01; ***P < 0.001.