Programming of CD8+ T Cell Tolerance by B Cell APC

描述(申请人提供)：血液病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，也可以在转移到宿主ARC后间接呈递，每种呈递方式都伴随着根本不同的信号。对于幼稚的CD8+T细胞，这些事件的结果可以决定是否通过各种耐受机制诱导有效的抗肿瘤反应，或使其功能沉默。目前，我们对正常B细胞或其转化的B细胞、淋巴瘤和骨髓瘤的抗原提呈细胞(APC)能力及其对体内初级抗原特异性CD8+T细胞的影响的认识都存在显著差距。这一应用基于可靠的实验模型，并有强大的初步数据支持，提出了一种假设，即在生理条件下，正常B细胞通过一种新的机制有效地在NATve CD8+T细胞中编程持久的耐受状态，该机制涉及一种新的机制，该机制导致TCR近端信号机制的初级扩张和随后TCR近端信号机制与克隆后代中下游细胞毒效应功能的解偶联。我们进一步认为，淋巴瘤利用这一相同的途径来清除现有CD8+T细胞库中能够识别转化过程中出现的大量抗原的克隆。因此，本研究的目的是了解正常和转化的原代B细胞在体内生理条件下如何诱导CD8+T细胞耐受。利用一种新型的体内转基因系统，在原代B细胞上表达模型抗原，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CDS 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)建立预防或克服B细胞诱导CD8+T细胞耐受的方法。这些研究的结果将为了解正常和转化的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.