Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, USA.
J Biol Chem. 2011 Oct 7;286(40):34883-92. doi: 10.1074/jbc.M111.276329. Epub 2011 Aug 17.
Artificial antigen-presenting cells (aAPCs) are an emerging technology to induce therapeutic cellular immunity without the need for autologous antigen-presenting cells (APCs). To fully replace natural APCs, an optimized aAPC must present antigen (signal 1), provide costimulation (signal 2), and release cytokine (signal 3). Here we demonstrate that the spatial and temporal characteristics of paracrine release of IL-2 from biodegradable polymer aAPCs (now termed paAPCs) can significantly alter the balance in the activation and proliferation of CD8+ and CD4+ T cells. Paracrine delivery of IL-2 upon T cell contact with paAPCs induces significant IL-2 accumulation in the synaptic contact region. This accumulation increases CD25 (the inducible IL-2 Rα chain) on responding T cells and increases proliferation of CD8+ T cells in vitro to levels 10 times that observed with equivalent amounts of bulk IL-2. These CD8+ T cell responses critically depend upon close contact of T cells and the paAPCs and require sustained release of low levels of IL-2. The same conditions promote activation-induced cell death in CD4+ T cells. These findings provide insight into the response of T cell subsets to paracrine IL-2.
人工抗原呈递细胞 (aAPC) 是一种新兴技术，可在无需自体抗原呈递细胞 (APC) 的情况下诱导治疗性细胞免疫。为了完全替代天然 APC，优化的 aAPC 必须呈递抗原 (信号 1)、提供共刺激 (信号 2) 并释放细胞因子 (信号 3)。在这里，我们证明了 IL-2 的旁分泌释放从可生物降解聚合物 aAPC（现在称为 paAPC）的时空特征可以显著改变 CD8+和 CD4+T 细胞的激活和增殖的平衡。T 细胞与 paAPC 接触时旁分泌 IL-2 的传递会在突触接触区域引起显著的 IL-2 积累。这种积累增加了响应 T 细胞上的 CD25（诱导型 IL-2 Rα 链），并增加了体外 CD8+T 细胞的增殖，达到与等量 bulk IL-2 观察到的水平的 10 倍。这些 CD8+T 细胞反应严重依赖于 T 细胞和 paAPC 的紧密接触，并需要持续释放低水平的 IL-2。相同的条件促进了 CD4+T 细胞中的激活诱导的细胞死亡。这些发现为 T 细胞亚群对旁分泌 IL-2 的反应提供了深入了解。
