Programming of CD8+ T Cell Tolerance by B Cell APC

描述（由申请人提供）：血液病对免疫系统构成了独特的挑战，因为它们可以将抗原直接呈递给宿主T细胞，也可以间接转移到宿主ARC，每种呈递方式的信号基本不同。对于初始CD8+ T细胞，这些事件的结果可以决定有效的抗肿瘤反应是被诱导，还是通过各种耐受性机制在功能上沉默。目前，我们对正常B细胞或其转化的对应物，淋巴瘤和骨髓瘤的抗原呈递细胞（APC）能力的理解，以及这对体内原发性抗原特异性CD8+ T细胞的影响，都存在显著的差距。本研究基于一个强大的实验模型和强有力的初步数据，提出了一个假设，即在生理条件下，正常B细胞通过一种新机制有效地在原生CD8+ T细胞中编程持久的耐受状态，该机制涉及信号的传递，导致TCR近端信号机制的初级扩增和随后从克隆后代的下游细胞毒性效应功能中解耦。我们进一步提出，淋巴瘤利用相同的途径清除能够识别转化过程中产生的大量抗原的克隆的CD8+ T细胞库。因此，本研究的目的是了解正常和转化的原代B细胞是如何在体内生理条件下诱导CD8+ T细胞耐受的。利用一种新颖的体内转基因系统，在原代B细胞上表达一种模型抗原，我们将追求以下目标：目的1)确定B细胞诱导CD8+ T细胞耐受的确切途径；目的2)确定CD8+ T细胞耐受表型的分子缺陷；目的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；目的4)建立可以阻止或克服B细胞诱导CD8+ T细胞耐受的方法。这些研究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。

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.