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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).

总结