TNF Processing in Pulmonary Immunopathology

描述（由申请方提供）：呼吸道病毒（如流感病毒，特别是高致病性毒株）感染导致相当严重的肺部免疫病理学，其中很大一部分是由宿主T细胞应答引起的。这种肺损伤是此类感染临床结局的重要决定因素。我们已经开发了一种模型，以区分肺损伤，这是特别是由于CD 8 + T细胞识别肺上皮细胞上的病毒抗原和T细胞效应活性，从而触发，从这导致从病毒本身的细胞病变的影响。在这个提议中，我们的目标是扩展CD 8 + T细胞介导的损伤的表征，以剖析在流感肺炎的存在下与T细胞应答相关的复杂免疫病理过程。我们已经发现高度损伤和最小损伤的T细胞群体在将跨膜TNF加工成其可溶形式的阈值方面存在显著差异。作为原理的证明，我们已经开发了专门表达不可切割的跨膜形式的TNF的CD 8 + T细胞，并且已经观察到损伤潜力的显著降低。由这些T细胞触发的病理学显著的是显著的间质/隔膜细胞浸润，而没有肺泡腔的显著浸润，并且没有水肿或出血的证据。此外，虽然WT T细胞介导的损伤的特征在于在T细胞接合后的前12-24小时内PMN的瞬时积累，随后是巨噬细胞的急剧积累，但这种PMN流入在转移突变T细胞后并不明显。在突变T细胞的接受者中，气体交换仅轻度受损。我们假设跨膜TNF的处理阈值决定了CD 8 + T细胞识别后损伤的严重程度。我们进一步假设，以抗原特异性方式产生的可溶性TNF介导的增强损伤的机制是肺泡上皮细胞响应T细胞识别诱导中性粒细胞趋化因子表达，这导致早期和短暂的中性粒细胞募集到肺泡腔。这似乎是由TNF-R2（p75）介导的，导致ERK活化和Egr-1表达旺盛。我们将研究WT和突变型CD 8 + T细胞群，以及表达突变型TNF受体的各种转基因小鼠，以了解CD 8 + TNF加工成可溶性物质如何引发严重的肺损伤，以及调节机制。

DESCRIPTION (provided by applicant): Infection with respiratory viruses such as with influenza, particularly the highly pathogenic strains, results in considerable pulmonary immunopathology, a large component of which results from the host T cell responses. This lung injury is an important determinant of clinical outcome in such infections. We have developed a model to distinguish the lung injury that is specifically due to CD8+ T cell recognition of viral antigen on lung epithelium and T cell effector activities triggered thereby, from that which results from the cyopathic effects of the virus itself. In this proposal we aim to extend the characterization of CD8+ T cell mediated injury to dissect the complex immunopathologic processes associated with T cell responses in the presence of influenza pneumonia. We have found a significant difference between highly injurious and minimally injurious T cell populations in their threshold for processing transmembrane TNF to its soluble form. As a proof of principle, we have developed CD8+ T cells which exclusively express a non-cleavable transmembrane form of TNF, and have observed a marked reduction in injury potential. The pathology triggered by these T cells is remarkable for significant interstitial/septal cellular infiltration without significant infiltration of the alveolar space and without evidence of edema or hemorrhage. Furthermore, while WT T cell-mediated injury is characterized by transient accumulation of PMNs in the first 12-24 hours after T cell engagement, followed by dramatic accumulation of macrophages, this PMN influx was not evident after transfer of the mutant T cells. Gas exchange was only mildly impaired in recipients of the mutant T cells. We hypothesize that the threshold for processing of transmembrane TNF determines the severity of the injury after CD8+ T cell recognition. We further hypothesize that the mechanism of enhanced injury mediated by soluble TNF produced in an antigen-specific fashion is the induction of neutrophil chemoattractant expression by alveolar epithelial cells, in response to T cell recognition, which leads to early and transient neutrophil recruitment to the alveolar space. This appears to mediated by TNF-R2 (p75) leading to exuberant ERK activation and Egr-1 expression. We will study WT and mutant CD8+ T cell populations, and a variety of transgenic mice expressing mutant TNF receptors in order to understand how CD8+ TNF processing to the soluble species triggers severe lung injury, and the mechanisms of regulation.