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
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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
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CD8
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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.
The dysregulation of store-operated Ca2+ entry (SOCE) promotes cancer progression by changing Ca2+ levels in the cytosol or endoplasmic reticulum. Stromal interaction molecule 1 (STIM1), a component of SOCE, is upregulated in several types of cancer and responsible for cancer cell migration, invasion, and metastasis. To explore the impact of STIM1-mediated SOCE on the turnover of focal adhesion (FA) and cell migration, we overexpressed the wild-type and constitutively active or dominant negative variants of STIM1 in an osteosarcoma cell line. In this study, we hypothesized that STIM1-mediated Ca2+ elevation may increase cell migration. We found that constitutively active STIM1 dramatically increased the Ca2+ influx, calpain activity, and turnover of FA proteins, such as the focal adhesion kinase (FAK), paxillin, and vinculin, which impede the cell migration ability. In contrast, dominant negative STIM1 decreased the turnover of FA proteins as its wild-type variant compared to the cells without STIM1 overexpression while promoting cell migration. These unexpected results suggest that cancer cells need an appropriate amount of Ca2+ to control the assembly and disassembly of focal adhesions by regulating calpain activity. On the other hand, overloaded Ca2+ results in excessive calpain activity, which is not beneficial for cancer metastasis.
Background: Concerns about the effects of nanoparticles (NPs) on human health are being raised by researchers because the risks of nanocosmetics like sunscreen are unknown. Methods: We explored the association between urinary oxidative stress markers and exposure of cosmetics salesclerks to 20 cosmetics which might contain titanium dioxide (TiO2)/zinc oxide (ZnO) NPs. We then recruited 40 cosmetics salesclerks and 24 clothing salesclerks and categorized them based on their exposure to ZnO and TiO2 NPs. Results: Nineteen and fifteen samples met the EU definition for TiO2 and ZnO nanomaterials, respectively. Participants with a higher co-exposure index of ZnO and TiO2 NPs had a significantly higher base level of urinary 8-hydroxy-2'-deoxyguanosin (8-OHdG) concentrations than the lower co-exposure group (5.82 vs. 2.85 ng/mL, p < 0.001). After potential confounding factors had been adjusted for, the TiO2 and ZnO NP co-exposure index was significantly positively associated with the urinary 8-OHdG base concentration (β = 0.308, 95% CI = 0.106 to 0.510) and the creatinine-adjusted concentration (β = 0.486, 95% CI = 0.017 to 0.954). Conclusion: Current evidence suggests that the likelihood of harm from using sunscreens containing nanoparticles might result in higher urinary 8-OHdG. However, our limited number and types of sample cosmetics might underestimate the risk.
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