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：
10625439
负责人：
Alice Oliffson Kamphorst
金额：
$ 65.29万
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/10625439
关键词：
Ablation Address Affect Alleles Antigen Targeting Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmunity Biological CD28 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes 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 chemokine chronic infection differential expression exhaust experience immunological intervention improved in vivo inducible gene expression 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).

概括最近的发现确定了编程细胞死亡（PD）-1+ CD8 T细胞识别肿瘤或慢性病原体具有劳动分裂：T细胞因子（TCF）-1+ PD-1+ CD8 T细胞充当内存样资源细胞和TCF-1NEG PD-1+ CD8 T细胞具有效应子样函数。 TCF-1+ PD-1+ CD8 T细胞自我更新和分化为效应子样和末端分化/耗尽的TCF-1NEG PD-1+ CD8 T细胞。 TCF-1+ 记忆样细胞具有高表达CD28，我们已经表明，在PD-1靶向疗法中CD28 重现CD8 T细胞反应需要共刺激。另外，内存样细胞具有高 ICO的表达和与卵泡辅助CD4 T细胞相似的基因表达程序。我们的初步数据表明，在既定的慢性淋巴细胞脉络膜宿主炎病毒（LCMV）感染中，连续CD28信号传导是差异化和自我更新类TCF-1+内存样PD-1+ CD8 T 细胞。相反，ICOS信号传导减少了分化为效应类细胞。记忆样细胞如何选择在自我更新和分化之间，以及如何将分化转化为效应类细胞很关键问题。除了一组独特的共刺激分子外，TCF-1+记忆样细胞还表达不同的趋化因子/细胞因子受体集。根据这些数据和现场的知识差距，我们提出了定义共刺激在PD-1+ CD8 T细胞维持和分化中的作用（AIM 1）和发现细胞相互作用的影响（AIM 2）。在AIM 1中，我们将确定CD28和ICO如何共刺激会影响TCF-1+内存样PD-1+ CD8 T细胞，并识别T细胞命运的转录调节剂。在AIM 2中，我们将使用公正的方法来识别TCF-1+内存样PD-1+ CD8 T的细胞相互作用细胞在体内和探测这些相互作用对T细胞命运决策的生物学后果。 XCL-1，a XCR1+树突状细胞（DC1）的化学吸引剂用TCF-1+记忆样细胞高度表达通过CD28信号。我们将解决DC1抗原表现和XCL-1生产在本地化中的作用， 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（慢性感染，癌症，自身免疫，移植和过敏）中的免疫疗法。