Identification of progenitor CD4 T cells that support response to chronic antigen

鉴定支持慢性抗原反应的 CD4 T 祖细胞

• 批准号: 10449403
• 负责人: Takeshi Egawa
• 金额: $ 19.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449403
• 关键词: Acute; Adoptive Cell Transfers; Antigens; BCL6 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chronic; Chronic Phase; Effector Cell; Epigenetic Process; Eragrostis; Helper-Inducer T-Lymphocyte; Immune response; Immunization; Impairment; Infection; Lymphocytic choriomeningitis virus; Maintenance; Memory; Modeling; Mus; PD-1 blockade; PRDM1 gene; Phase; Play; Population; Proteins; Reporter; Role; Supporting Cell; T cell differentiation; T cell response; T memory cell; T-Lymphocyte Subsets; Testing; Tumor Immunity; Virus Diseases; acute infection; adaptive immune response; chronic infection; effector T cell; immune checkpoint blockade; memory CD4 T lymphocyte; pathogen; population based; progenitor; programmed cell death ligand 1; programmed cell death protein 1; response; self-renewal; single-cell RNA sequencing; stem; stem cells; transcription factor; tumor

Abstract Durable immune response by both CD4 and CD8 T cells is required for the control of chronic infection or tumors. In the past few years, multiple independent studies have identified a subset of progenitor-like or stem- like TCF-1+ PD-1+ CD8 T cells in both chronic viral infections and tumors. These progenitor CD8 T cells continue generating new effector CD8 T cells to support long-term CD8 T cell responses to persisting antigens (Ags). They are also capable of eliciting robust effector responses by the immune checkpoint blockade targeting the PD-1 to PD-L1 interaction. However, it remains unknown how CD4 T cell responses to persistent Ag are maintained, or whether a specialized subset of progenitor-like CD4 T cells equivalent to TCF-1+ progenitor CD8 T cells exists to support the durability of CD4 T cell response or respond to the PD-1 blockade. We have found that the transcription factor BCL6 is essential for the durable CD4 T cell effector response to chronic LCMV infection, implying that an analogous progenitor CD4 T cells are present in the face of chronic antigen stimulation. We propose to identify such a CD4 T cell population and conduct the initial characterization of the unique CD4 T cell subset.

摘要 CD 4和CD 8 T细胞的持久免疫应答是控制慢性感染或 肿瘤的在过去的几年里，多项独立的研究已经确定了一个祖细胞样或干细胞的子集， 如慢性病毒感染和肿瘤中的TCF-1+ PD-1+ CD 8 T细胞。这些祖细胞CD 8 T细胞 继续产生新的效应CD 8 T细胞，以支持对持续抗原的长期CD 8 T细胞应答 （Ags）.它们还能够通过免疫检查点阻断引发强大的效应子应答 靶向PD-1与PD-L1相互作用。然而，目前尚不清楚CD 4 T细胞如何对持续性免疫应答。 抗原是否维持，或者是否有一个专门的祖细胞样CD 4 T细胞亚群相当于TCF-1+ 祖CD 8 T细胞的存在是为了支持CD 4 T细胞应答的持久性或响应PD-1阻断。 我们已经发现转录因子BCL 6对于持久的CD 4 T细胞效应器应答是必需的， 慢性LCMV感染，这意味着一个类似的祖CD 4 T细胞存在于慢性LCMV感染的脸。 抗原刺激我们建议识别这样的CD 4 T细胞群，并进行初步的研究。 这是对独特的CD 4 T细胞亚群的表征。