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

Abstract

When dormant naïve T cells first become activated by antigenpresenting 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.

Stable Epigenetic Programming of Effector and Central Memory CD4 T Cells Occurs Within 7 Days of Antigen Exposure In Vivo

“…In this study, Tem cells exhibit much higher expression of the Il7r, IL2ra and Il2b genes than Tcm cells (Figures 7A-C) consistent with the previous observation that Tcm cells lack IL-2Ra expression (5,26). This is highly significant because we recently demonstrated that IL-2/IL-7 signalling via the common gamma chain plays a crucial role in maintaining accessible sites in lineage-specific genes prior to T cell differentiation (5). Without this priming for T cell differentiation, Tcm cells may be left in limbo, unable to differentiate, but progress towards an equally important fate of establishing and maintaining a plastic memory of TCR activation, before any lineage-commitment decision has been made.…”

“…Once immunological memory has been established in T cells, it is remarkably stable in the absence of further TCR activation. In rapidly dividing cells cultured with IL-2 or IL-7, mDHSs recruit TFs that include ETS1, RUNX1, JUND and STAT5 which maintain an open chromatin environment rendered more accessible by histone H3K4me2 and H3K9ac (3,5). In the context of immune homeostasis, immunological priming of TM cells is likely to remain stable for decades in quiescent TM cells in the presence of lymph node derived IL-7 or tissue-derived IL-15 (5,(10)(11)(12).…”

“…During primary immune responses, effector T cells arise from naïve T cells (TN) when their antigen (Ag) -specific TCRs recognize Ag on Ag presenting cells (APCs) for the first time and undergo transformation over a 1-2 day period to become rapidly dividing T blast cells (TB) (1). During this process, the combination of TCR, CD28 and IL-2 signaling promotes the extensive reprograming of the T cell gene regulatory network, rendering immune response genes much more receptive to reactivation and enabling further differentiation to specialized Th cells (2)(3)(4)(5). Systemic bacterial or viral infections in vivo typically establish a Th1-polarizing environment whereby additional cytokines such as IL-12 induce expression of the Th1-lineagedefining transcription factor (TF) T-bet, and T-bet target genes such as Ifng (IFN-g), which reinforce Th1 status (6)(7)(8).…”

“…Furthermore, the level of CXCR5 expression negatively correlated with Il2ra expression. Il2radeficient T cells were able to efficiently generate CXCR5 + PD-1 -Tcm cells, but they only produced 10% of the normal proportion of T-bet high CXCR5 -Th1 cells (5,26). Whilst the development of these memory cell populations was characterised in fine detail, the molecular basis underlying the establishment and stable maintenance of memory in Tem and Tcm cells in vivo was never established.…”

Remodeling the chromatin landscape in T lymphocytes by a division of labor among transcription factors

“…The roles of STATs in both limiting and promoting gene expression became clear by the demonstration that STATs can also lead to unloading of p300 at enhancers of opposite lineages. Other reports suggest that IL‐2 signaling is essential for maintaining accessible chromatin regions at hundreds of gene regulatory elements of T cell differentiation pathways 141 . More specifically, IL‐2 signaling can activate AP‐1 and STAT5 proteins that can subsequently bind lineage‐determining transcription factors, depending on other proteins downstream of extracellular environments of T cells.…”