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 1

Wnt signaling alters human memory CD8+ T cell proliferation and differentiation.

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Wnt signaling alters human memory CD8+ T cell proliferation and differen...
(A) FACS-sorted human naive and memory CD8+ T cells were stained with CTV and stimulated with CD3/CD28 in DMSO (black), TWS119 (blue), and SKL2001 (red) for 7 days. Numbers represent the percentages of divided cells in each treatment. (B) Average proliferative response for each treatment (n = 5). Dunn’s test for multiple comparisons. (C) Memory CD8+ T cells in different treatments for 7 days were stained with phenotypic markers. Numbers represent the percentages of cells in each quadrant. (D) Quantitative RT-PCR analysis of Tcf7, Lef1, and Fzd7 in memory CD8+ T cells with or without Wnt agonist treatment on days 1, 3, and 5. Numbers are normalized to marker expression of the DMSO group at each corresponding time point. (E) Memory CD8+ T cells were stimulated with CD3/CD28 and treated with or without Wnt agonists for 7 days. β-Catenin and TCF1 levels were analyzed by flow cytometry. Numbers represent the MFI of each protein. (F) Average MFI of β-catenin and TCF1 in different treatment conditions (n = 4). Dunn’s test for multiple comparisons. #P < 0.05.