Programming of CD8+ T Cell Tolerance by B Cell APC

B 细胞 APC 对 CD8 T 细胞耐受性进行编程

• 批准号: 7428877
• 负责人: Stephen Philip Schoenberger
• 金额: $ 46万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7428877
• 关键词: Antigen-Presenting Cells; Antigens; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Behavior; Biochemical; Biological Models; CD8B1 gene; Cell physiology; Clonal Expansion; Condition; Cytokine Signaling; Data; Defect; Development; Distal; Evaluation; Event; Experimental Models; Expression Feature; Genetic; Hematologic Neoplasms; Human; Immune response; Immune system; Immunobiology; Immunotherapy; Inflammatory; Kinetics; Lead; Left; Lesion; Light; Lymphoma; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Mouse Strains; Multiple Myeloma; Nature; Neoplastic Cell Transformation; Outcome; Pathway interactions; Peripheral; Phenotype; Physiological; Process; Production; Research; Research Personnel; Signal Transduction; Signal Transduction Pathway; System; T-Lymphocyte; Transgenic Model; Transgenic Organisms; Tumor Necrosis Factor Ligand Superfamily Member 6; base; cytotoxic; in vivo; in vivo Model; large cell Diffuse non-Hodgkin' s lymphoma; leukemia/lymphoma; neoplastic; novel; novel strategies; perforin; prevent; programs; purge; response; transmission process; tumor

DESCRIPTION (provided by applicant): Hematologic cancers pose a unique challenge to the immune system, as they can present their antigens both directly to host T cells, or indirectly following transfer to host ARC, with fundamentally distinct signals accompanying each mode of presentation. For naive CD8+ T cells, the outcome of these events can determine whether an effective anti-tumor response is either induced, or rendered functionally silent through a variety of tolerance mechanisms. There are currently significant gaps in both our understanding of the antigen-presenting cells (APC) capacity of normal B cells or their transformed counterparts, lymphomas and myelomas, as well as the consequences of this for primary antigen-specific CD8+ T cells of in vivo. This application, based on a robust experimental model and supported by strong preliminary data, proposes the hypothesis that under physiological conditions, normal B cells efficiently program a durable state of tolerance in naTve CD8+ T cells through a novel mechanism involving transmission of signals that lead to primary expansion and subsequent uncoupling of the TCR proximal signaling machinery from the downstream cytotoxic effector functions in the clonal progeny. We further suggest that this same pathway is utilized by lymphomas to purge the available CD8+ T cell repertoire of clones capable of recognizing the multitude of antigens that arise during the process of transformation. The objective of this research is therefore to understand how normal and transformed primary B cells induce tolerance in CD8+ T cells under physiological conditions in vivo. Using a novel in vivo transgenic system that features expression of a model antigen on primary B cells, we will pursue the following aims: Aim 1) to characterize of the exact pathways in which B cells induce CD8+ T cell tolerance, Aim 2) to define the molecular defect underlying the tolerant phenotype of CDS T cells, Aim 3) to determine whether spontaneous lymphomas induce CD8+ T cell tolerance via the same pathway, and Aim 4) to establish methods through which the induction of CDS T cell tolerance by B cells can be prevented or overcome. The results of these studies will shed important new light on the APC function of normal and transformed B cells, and will allow the development of much-needed new strategies for enhancement of immune responses to B cell tumors.

描述（由申请人提供）：血液癌症对免疫系统提出了独特的挑战，因为它们可以直接将抗原呈递给宿主 T 细胞，或者在转移到宿主 ARC 后间接呈递抗原，每种呈递模式都伴随着根本不同的信号。对于初始 CD8+ T 细胞，这些事件的结果可以决定是否诱导有效的抗肿瘤反应，或通过各种耐受机制使其功能沉默。目前，我们对正常 B 细胞或其转化对应物、淋巴瘤和骨髓瘤的抗原呈递细胞 (APC) 能力的理解，以及其对体内初级抗原特异性 CD8+ T 细胞的影响，都存在显着差距。该应用基于稳健的实验模型并得到强有力的初步数据的支持，提出了这样的假设：在生理条件下，正常 B 细胞通过一种新颖的机制，有效地在天然 CD8+ T 细胞中编程持久的耐受状态，该机制涉及信号传输，导致初次扩增和随后 TCR 近端信号机制与克隆中下游细胞毒性效应器功能的解偶联。 后代。我们进一步表明，淋巴瘤利用相同的途径来清除可用的 CD8+ T 细胞克隆库，这些克隆能够识别转化过程中出现的多种抗原。因此，本研究的目的是了解正常和转化的原代 B 细胞如何在体内生理条件下诱导 CD8+ T 细胞的耐受性。使用一种新型体内转基因系统，其特征是在原代 B 细胞上表达模型抗原，我们将追求以下目标：目标 1) 表征 B 细胞诱导 CD8+ T 细胞耐受的确切途径，目标 2) 定义 CDS T 细胞耐受表型背后的分子缺陷，目标 3) 确定自发性淋巴瘤是否通过相同的途径诱导 CD8+ T 细胞耐受。 途径，目标 4) 建立可以预防或克服 B 细胞诱导 CDS T 细胞耐受的方法。这些研究的结果将为正常和转化 B 细胞的 APC 功能提供重要的新线索，并将允许开发急需的新策略来增强对 B 细胞肿瘤的免疫反应。