Programming of CD8+ T Cell Tolerance by B Cell APC

描述（由申请人提供）：血液系统癌症对免疫系统构成了独特的挑战，因为它们可以将其抗原直接呈递给宿主T细胞，或在转移至宿主ARC后间接呈递，每种呈递模式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应答，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，以及其对体内原代抗原特异性CD8+ T细胞的影响，都存在显著的差距。该申请基于稳健的实验模型并得到强有力的初步数据的支持，提出了在生理条件下，正常B细胞有效地编程了天然CD8+ T细胞中的持久耐受状态通过一种新的机制，涉及信号的传输，导致初级扩增和随后的解偶联的TCR近端信号机制从下游细胞毒性效应子功能的克隆T细胞，后代我们进一步表明，淋巴瘤利用这一相同的途径来清除能够识别转化过程中出现的大量抗原的克隆的可用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细胞如何在体内生理条件下诱导CD8+ T细胞耐受。使用以在原代B细胞上表达模型抗原为特征的新型体内转基因系统，我们将追求以下目标：目的1）表征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，以及目的4）建立通过其可以预防或克服由B细胞诱导CD8+ T细胞耐受的方法。这些研究的结果将为正常和转化的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细胞肿瘤的免疫应答。

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.