Department of Biomedical Engineering, Columbia University, 1210 Amsterdam Ave, New York, NY, 10027, USA.
Department of Biological Sciences, Columbia University, 1212 Amsterdam Ave, New York, NY, 10027, USA.
Biomaterials. 2023 Jan;292:121928. doi: 10.1016/j.biomaterials.2022.121928. Epub 2022 Nov 26.
Regulatory T cells (Tregs) provide an essential tolerance mechanism to suppress the immune response. Induced Tregs hold the potential to treat autoimmune diseases in adoptive therapy and can be produced with stimulating signals to CD3 and CD28 in presence of the cytokine TGF-β and IL-2. This report examines the modulation of human Treg induction by leveraging the ability of T cells to sense the mechanical stiffness of an activating substrate. Treg induction on polyacrylamide gels (PA-gels) was sensitive to the substrate's elastic modulus, increasing with greater material stiffness. Single-cell RNA-Seq analysis revealed that Treg induction on stiffer substrates involved greater use of oxidative phosphorylation (OXPHOS). Inhibition of ATP synthase significantly reduced the rate of Treg induction and abrogated the difference among gels while activation of AMPK (AMP-activated protein kinase) increased Treg induction on the softer sample but not on the harder sample. Treg induction is thus mechanosensitive and OXPHOS-dependent, providing new strategies for improving the production of these cells for cellular immunotherapy.
调节性 T 细胞（Tregs）提供了一种重要的耐受机制，以抑制免疫反应。诱导的 Tregs 具有在过继治疗中治疗自身免疫性疾病的潜力，并且可以通过刺激信号在 TGF-β和 IL-2 的存在下与 CD3 和 CD28 产生。本报告通过利用 T 细胞感知激活底物机械硬度的能力来检查人 Treg 诱导的调节。Treg 在聚丙烯酰胺凝胶（PA 凝胶）上的诱导对基质的弹性模量敏感，随着材料刚度的增加而增加。单细胞 RNA-Seq 分析显示，在较硬的基质上诱导 Treg 涉及更多的氧化磷酸化（OXPHOS）。ATP 合酶的抑制显著降低了 Treg 诱导的速度，并消除了凝胶之间的差异，而 AMPK（AMP 激活的蛋白激酶）的激活增加了较软样本上的 Treg 诱导，但不能增加较硬样本上的 Treg 诱导。因此，Treg 诱导是机械敏感和 OXPHOS 依赖性的，为改善这些细胞用于细胞免疫治疗的生产提供了新策略。
