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

摘要 最近的研究发现，程序性细胞死亡(PD)-1+CD8 T细胞识别肿瘤或慢性 病原体有分工：T细胞因子(TCF)-1+PD-1+CD8 T细胞作为记忆来源发挥作用 细胞和TCF-1neg PD-1+CD8T细胞具有效应器样功能。Tcf-1+PD-1+CD8 T细胞自我更新和 分化为效应器样和终末分化/更耗尽的TCF-1neg PD-1+CD8 T细胞。TCF-1+ 记忆样细胞高表达CD28，我们已经证明在PD-1靶向治疗期间CD28 CD8T细胞反应的恢复需要共刺激。此外，类记忆细胞具有很高的 ICOS的表达，以及与卵泡辅助CD4T细胞相似的基因表达程序。我们的 初步数据表明，在慢性淋巴细胞性脉络膜脑膜炎病毒(LCMV)感染期间， TCF-1+Memory-like PD-1+CD8 T的分化和自我更新需要持续的CD28信号 细胞。相反，ICOS信号会减少向效应器样细胞的分化。记忆类细胞如何选择 在自我更新和分化之间，以及如何调节分化为效应器样细胞是关键 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 一组独特的趋化因子/细胞因子受体。基于这些数据和该领域的知识差距，我们提出了 明确共刺激在PD-1+CD8 T细胞维持和分化中的作用(目标1)和 揭示细胞相互作用的影响(目标2)。在目标1中，我们将确定CD28和ICOS如何 共刺激作用影响TCF-1+记忆样PD-1+CD8 T细胞，并识别T细胞命运的转录调节因子。 在目标2中，我们将使用无偏见的方法来确定TCF-1+Memory-like PD-1+CD8 T的细胞相互作用 并探索这些相互作用对T细胞命运决定的生物学后果。XCL-1，a TCF-1+记忆样细胞高表达XCR1+树突状细胞趋化因子(Dc1)并受其调控 通过CD28信号传递。我们将讨论Dc1抗原提呈和XCL-1产生在定位中的作用， TCF-1+记忆样PD-1+CD8 T细胞的分化和自我更新了解以下决定因素 长期暴露在抗原下的T细胞的自我更新和分化将具有广泛的意义 许多病理疾病(慢性感染、癌症、自身免疫、移植和过敏)中的免疫疗法。

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).