Determinants of differentiation and maintenance of PD-1+ CD8 T cells

总结 最近的研究结果表明，识别肿瘤或慢性炎症的程序性细胞死亡（PD）-1+ CD 8 T细胞， 病原体有分工：T细胞因子（TCF）-1+ PD-1+ CD 8 T细胞作为记忆样资源 细胞和TCF-1 neg PD-1+ CD 8 T细胞具有效应子样功能。TCF-1+ PD-1+ CD 8 T细胞自我更新， 分化为效应样和终末分化/更多耗尽的TCF-1阴性PD-1+ CD 8 T细胞。TCF-1 记忆样细胞具有高表达的CD 28，我们已经证明，在PD-1靶向治疗期间，CD 28 共刺激是CD 8 T细胞应答的再激活所必需的。此外，记忆样细胞具有高 ICOS的表达，以及与滤泡辅助性CD 4 T细胞相似的基因表达程序。我们 初步数据表明在确立的慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染期间， TCF-1+记忆样PD-1+ CD 8 T细胞的分化和自我更新需要持续的CD 28信号传导 细胞相比之下，ICOS信号转导减少了向效应子样细胞的分化。类记忆细胞如何选择 自我更新和分化之间的关系，以及如何调节分化为效应样细胞是至关重要的 问题.除了一组独特的共刺激分子外，TCF-1+记忆样细胞还表达一种 不同的趋化因子/细胞因子受体。基于这些数据和该领域的知识差距，我们建议 确定共刺激在PD-1+ CD 8 T细胞的维持和分化中的作用（目的1）， 揭示细胞相互作用的影响（目标2）。在目标1中，我们将确定CD 28和ICOS 共刺激影响TCF-1+记忆样PD-1+ CD 8 T细胞并鉴定T细胞命运的转录调节因子。 在目标2中，我们将使用无偏的方法来鉴定TCF-1+记忆样PD-1+ CD 8 T细胞的细胞相互作用。 细胞在体内和探测这些相互作用的T细胞命运决定的生物学后果。XCL-1，a XCR 1+树突状细胞（DC 1）的趋化因子由TCF-1+记忆样细胞高度表达，并被调节 CD 28信号我们将讨论DC 1抗原呈递和XCL-1产生在定位中的作用， TCF-1+记忆样PD-1+ CD 8 T细胞的分化和自我更新。了解的决定因素 长期暴露于抗原的T细胞的自我更新和分化将具有广泛的意义， 免疫疗法在许多病理（慢性感染，癌症，自身免疫，移植和过敏）。

SUMMARY Recent findings identified that Programmed Cell Death (PD)-1+ CD8 T cells recognizing tumor or chronic pathogens have a division of labor: T cell factor (TCF)-1+ PD-1+ CD8 T cells function as memory-like resource cells and TCF-1neg PD-1+ CD8 T cells have effector-like function. TCF-1+ PD-1+ CD8 T cells self-renew and differentiate into effector-like and terminally differentiated/more exhausted TCF-1neg PD-1+ CD8 T cells. TCF-1+ memory-like cells have high expression CD28, and we have shown that during PD-1 targeted therapies CD28 costimulation is required for the reinvigoration of CD8 T cell responses. In addition, memory-like cells have high expression of ICOS, and a gene expression program with similarities to follicular helper CD4 T cells. Our preliminary data suggest that during established chronic lymphocytic choriomeningitis virus (LCMV) infection, continuous CD28 signaling is required for differentiation and self-renewal of TCF-1+ memory-like PD-1+ CD8 T cells. In contrast, ICOS signaling diminishes differentiation into effector-like cells. How memory-like cells choose between self-renewal and differentiation, and how to modulate differentiation into effector-like cells are critical questions. In addition to a unique set of costimulatory molecules, TCF-1+ memory-like cells also express a distinct set of chemokine/cytokine receptors. Based on these data and the knowledge gap in the field, we propose to define the role of costimulation in the maintenance and differentiation of PD-1+ CD8 T cells (Aim 1) and uncover the impact of cellular interactions (Aim 2). In Aim 1, we will determine how CD28 and ICOS costimulation affect TCF-1+ memory-like PD-1+ CD8 T cells and identify transcriptional regulators of T cell fate. In Aim 2, we will use an unbiased approach to identify cellular interactions of TCF-1+ memory-like PD-1+ CD8 T cells in vivo and probe the biological consequences of these interactions for T cell fate decisions. XCL-1, a chemoattractant for XCR1+ dendritic cells (DC1) is highly expressed by TCF-1+ memory-like cells and modulated by CD28 signaling. We will address the role of DC1 antigen presentation and XCL-1 production on localization, differentiation and self-renewal of TCF-1+ memory-like PD-1+ CD8 T cells. Understanding the determinants of self-renewal and differentiation of T cells chronically exposed to antigens would have broad implications for immunotherapies in many pathologies (chronic infections, cancer, autoimmunity, transplantation and allergy).