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 3

Wnt activation enhances CD8+ T cell polyfunctionality independently of inhibitory receptor and DC signaling.

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Wnt activation enhances CD8+ T cell polyfunctionality independently of i...
(A) CD8+ T cells from HLA-A*0201 donors were stimulated with autologous moDCs pulsed with influenza M1 peptide for 7 days (n = 4). Tetramer-positive cells were subsequently assessed for polyfunctionality by restimulation with M1-pulsed HLA-A*0201+ T2 cells. Blue, red, and black boxes and numbers indicate IFN-γ+, TNF-α+, and IL-2+ cells, respectively. Purple numbers indicate the percentages of IFN-γ+TNF-α+ double-positive cells. Pie charts represent the T cell polyfunctionality profile induced by different treatments. Red slices indicate the proportion of cells positive for four effector functions (IFN-γ+, TNF-α+, IL-2+, and CD107a+). 0, 1, 2, 3, 4 are defined as the number of positive cytokine. (B) Percentages of IFN-γ–, TNF-α–, IL-2-, and CD107a-positive cells among M1-specific cells (n = 4). Dunn’s test for multiple comparisons. (C) Peripheral blood mononuclear cells from HLA-A*0201 donors were collected and stimulated with M1 peptide for 7 days in DMSO and isotype control antibodies or in SKL2001 with PD-1 blockade antibodies or isotype control antibodies. Cells were harvested and further stimulated by M1-pulsed T2 cells to analyze polyfunctionality (n = 4). (D) MFI of IFN-γ, TNF-α, and IL-2 in corresponding cytokine-positive cells in different treatment conditions (n = 4). Mann-Whitney U test. (E) HLA-A*0201 CD8+ T cells were stimulated with M1-pulsed aAPCs for 7 days in different treatment conditions and analyzed for polyfunctionality. (F) MFI of individual cytokines in corresponding cytokine-positive cells (n = 4). Mann-Whitney U test. (G) Cytotoxicity assay showed enhanced cytotoxicity in Wnt agonist–treated M1-specific T cells. *P < 0.05; **P < 0.01; ***P < 0.001. #P < 0.05 by Dunn’s test.