IL‐2/IL‐7‐inducible factors pioneer the path to T cell differentiation in advance of lineage‐defining factors

摘要

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.