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

基本信息

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
项目类别：
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&apos s lymphoma leukemia/lymphoma neoplastic novel novel strategies perforin prevent programs purge response transmission process tumor

项目摘要

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）：血液学癌症对免疫系统构成了独特的挑战，因为它们可以直接向宿主T细胞呈现抗原，或在转移到宿主ARC之后间接地呈现，并具有从根本上具有不同信号，伴随每种表现方式。对于幼稚的CD8+ T细胞，这些事件的结果可以确定是否通过各种耐受机制诱导有效的抗肿瘤反应，或在功能上呈现。目前，我们对正常B细胞的抗原呈递细胞（APC）或其转化后对应物，淋巴瘤和脊髓瘤的能力以及对原代抗原特异性CD8+ T细胞的后果都存在显着差距。该应用基于强大的实验模型并得到强有力的初步数据的支持，它提出了以下假设：在生理条件下，正常B细胞有效地对NATVE CD8+ T细胞中耐受性的持久状态进行了耐受性，涉及信号传播的新型机制，这些机制会导致TRCR的主要膨胀，并随后的TCR信号机械效应，从后代。我们进一步建议，通过淋巴瘤利用相同的途径来清除能够识别在转化过程中出现的多种抗原的克隆的可用CD8+ T细胞库。因此，这项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。使用新型的体内转基因系统，该系统具有特征在原代B细胞上表达模型抗原的表达，我们将追求以下目的：目的1）表征B细胞诱导CD8+ T细胞耐受性的确切途径的确切途径，目的2）定义分子缺陷，以确定CD的耐受性CD8，以确定CD的耐受性3）是否是cd的3）。途径和目标4）建立可以防止或克服B细胞诱导CD T细胞耐受性的方法。这些研究的结果将为正常B细胞和转化的B细胞的APC功能提供重要的新启示，并将允许发展急需的新策略，以增强对B细胞肿瘤的免疫反应。