CD8 T cell fate decision instructed by IL-2

摘要 作为对病毒感染或疫苗接种的反应，抗原(Ag)特异性CD8T细胞处于低水平 频率经历快速的克隆性扩张。而大多数激活的CD8T细胞成为终末期 分化的效应T细胞扩增后死亡，Ag清除后死亡，其中一小部分 作为记忆细胞(TMEM)持续存在，有助于长期保护。然而，它仍然不完全 了解细胞外刺激如何通过TCR和细胞因子受体建立基因调控 决定激活的CD8 T细胞命运的网络。这笔赠款的总体目标是剖析 TCR和IL-2R信号协同调节CD8 T细胞的分子和细胞机制 通过控制Tcf7编码的关键转录因子Tcf-1进行分化。我们将测试 假设抗原和IL-2诱导的信号之间的协同作用，而不是IL-15，特别是 在启动过程中诱导一组转录因子的表达和转录水平的表观遗传变化 TCF7基因座中的消音器元件。建立稳定的Tcf7抑制需要刺激- IL-2R信号的响应性增强，从而建立稳定的teff或TMEM特异性基因 在诱导细胞外在刺激作为免疫衰变后能够稳定维持的调节电路 响应会分解或变得平衡。这些研究将为这个长期存在的问题提供见解 CD8 T细胞分化的分子机制及其在编程中的潜在应用 免疫疗法。

Abstract In response to viral infection or vaccination, antigen(Ag)-specific CD8 T cells that are present at low frequencies undergo rapid clonal expansion. While the majority of activated CD8 T cells become terminally differentiated effector T (TEFF) cells following expansion and die after Ag clearance, a small fraction of them persists as memory cells (TMEM) that contribute to long-term protection. However, it remains incompletely understood how cell-extrinsic stimuli through TCR and cytokine receptors establish the gene regulatory networks that determine the fates of activated CD8 T cells. The overall goal of this grant is to dissect the molecular and cellular mechanisms by which TCR and IL-2R signaling cooperatively regulates CD8 T cell differentiation through the control of the critical transcription factor TCF-1 encoded by Tcf7. We will test the hypothesize that cooperative action between signals induced by antigen and IL-2, but not IL-15, specifically during priming induces expression of a set of transcription factors and epigenetic changes at a transcriptional silencer element in the Tcf7 locus. The establishment of stable Tcf7 repression requires the stimulation- responsive enhancement of IL-2R signaling, which establishes steady the TEFF- or TMEM-specific gene regulatory circuitry that can be stably maintained after the inducing cell extrinsic stimuli decays as immune responses resolve or become equilibrated. These studies will provide insights into the long standing question of the molecular mechanisms of CD8 T cell differentiation and potential application to programming improved immunotherapies.