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

PD-1 CD8 T 细胞分化和维持的决定因素

基本信息

批准号：
10298161
负责人：
Alice Oliffson Kamphorst
金额：
$ 65.4万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298161
关键词：
Ablation Address Affect Alleles Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmunity Biological CD28 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cell Differentiation process Cell physiology Cells Chemotactic Factors Chimeric Proteins Chronic Coculture Techniques Cytokine Receptors Data Dendritic Cells Detection Deterioration Disease Exposure to Gene Expression Genetic Transcription Hypersensitivity Immune Immunotherapy Interleukin-2 Intervention Knowledge Label Lymphocytic choriomeningitis virus Maintenance Malignant Neoplasms Memory Molecular Pathology Pathway interactions Phase Phenotype Play Positioning Attribute Production Resources Role Shapes Signal Transduction Stromal Cells T cell differentiation T cell response T cell transcription factor 1 T-Cell Activation T-Lymphocyte TCF Transcription Factor Testing Transplantation Virus Virus Diseases XCL1 gene XCR1 gene base cell type chemokine chronic infection differential expression exhaust experience immunological intervention improved in vivo mouse model novel pathogen programmed cell death protein 1 programs receptor self renewing cell self-renewal targeted treatment tool tumor

项目摘要

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).

概括最近的研究发现，程序性细胞死亡 (PD)-1+ CD8 T 细胞识别肿瘤或慢性病病原体有分工：T细胞因子（TCF）-1+ PD-1+ CD8 T细胞充当记忆样资源细胞和 TCF-1neg PD-1+ CD8 T 细胞具有效应样功能。 TCF-1+ PD-1+ CD8 T 细胞自我更新分化为效应样细胞和终末分化/更耗竭的 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靶向治疗过程中CD28 重振 CD8 T 细胞反应需要共刺激。此外，类似记忆的细胞具有很高的 ICOS 的表达，以及与滤泡辅助 CD4 T 细胞相似的基因表达程序。我们的初步数据表明，在慢性淋巴细胞脉络膜脑膜炎病毒（LCMV）感染期间， TCF-1+ 记忆样 PD-1+ CD8 T 的分化和自我更新需要连续的 CD28 信号传导细胞。相反，ICOS 信号传导会减少向效应样细胞的分化。类似记忆的细胞如何选择自我更新和分化之间，如何调节分化为效应样细胞至关重要问题。除了一组独特的共刺激分子外，TCF-1+ 记忆样细胞还表达一组不同的趋化因子/细胞因子受体。根据这些数据和该领域的知识差距，我们提出定义共刺激在 PD-1+ CD8 T 细胞的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，我们将使用公正的方法来识别 TCF-1+ 记忆样 PD-1+ CD8 T 的细胞相互作用体内细胞并探讨这些相互作用对 T 细胞命运决定的生物学影响。 XCL-1，一个 XCR1+ 树突状细胞 (DC1) 的趋化剂由 TCF-1+ 记忆样细胞高度表达并受到调节通过 CD28 信号传导。我们将讨论 DC1 抗原呈递和 XCL-1 生产在定位中的作用， 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对许多病理学的免疫疗法（慢性感染、癌症、自身免疫、移植和过敏）。