IL-2/IL-7-inducible factors pioneer the path to T cell differentiation in advance of lineage-defining factors.
IL-2/IL-7-inducible factors pioneer the path to T cell differentiation in advance of lineage-defining factors.
复制标题
IL-2/IL-7诱导因子在谱系定义因子之前开辟了T细胞分化的途径。
DOI：
10.15252/embj.2020105220
复制
发表时间：
2020-11-16
期刊：
影响因子：
--
通讯作者：
Cockerill PN
中科院分区：
文献类型：
--
作者：
Bevington SL;Keane P;Soley JK;Tauch S;Gajdasik DW;Fiancette R;Matei-Rascu V;Willis CM;Withers DR;Cockerill PN
当休眠的幼稚T细胞首次被抗原呈递细胞激活时，它们表达自分泌生长因子IL-2，将其转化为快速分裂的效应T细胞。在这个过程中，数百个基因经历表观遗传重编程以有效激活，并且在作为记忆T细胞返回静止状态后也可能重新激活。然而，IL-2和T细胞受体信号传导对这一过程的相对贡献尚不清楚。在这里，我们表明，IL-2信号传导是维持开放的染色质在数百个基因调控元件，其中许多控制随后的刺激依赖性替代途径的T细胞分化所必需的。我们证明，IL-2激活AP-1和STAT 5的结合位点，这些位点随后可以结合谱系决定转录因子，这取决于局部T细胞环境中存在哪些其他外部因子。一旦建立，也可以通过基质来源的稳态细胞因子IL-7维持启动，如果随后在体内删除IL-7 r，则启动减少。因此，IL-2不仅仅是一种生长因子;它为T细胞分化和免疫记忆奠定了基础。细胞因子信号传导需要维持染色质在谱系决定转录因子的结合/调节位点的可及性，使其在T细胞命运决定中具有更有指导性的作用，而不仅仅是下游作用。
When dormant naïve T cells first become activated by antigen‐presenting cells, they express the autocrine growth factor IL‐2 which transforms them into rapidly dividing effector T cells. During this process, hundreds of genes undergo epigenetic reprogramming for efficient activation, and also for potential reactivation after they return to quiescence as memory T cells. However, the relative contributions of IL‐2 and T cell receptor signaling to this process are unknown. Here, we show that IL‐2 signaling is required to maintain open chromatin at hundreds of gene regulatory elements, many of which control subsequent stimulus‐dependent alternative pathways of T cell differentiation. We demonstrate that IL‐2 activates binding of AP‐1 and STAT5 at sites that can subsequently bind lineage‐determining transcription factors, depending upon what other external factors exist in the local T cell environment. Once established, priming can also be maintained by the stroma‐derived homeostatic cytokine IL‐7, and priming diminishes if Il7r is subsequently deleted in vivo. Hence, IL‐2 is not just a growth factor; it lays the foundation for T cell differentiation and immunological memory. Cytokine signaling is required to maintain chromatin accessibility at binding/regulatory sites for lineage‐determining transcription factors, giving it a more instructive and not just downstream role in T cell fate determination.