The role of natural killer T cells in the innate response to lung infection

描述（由申请人提供）：不变的自然杀伤T细胞（iNKT细胞）是一种迷人的先天样T淋巴细胞群，可识别由CD 1d（一种I类抗原呈递分子）呈递的糖脂。iNKT细胞缺陷的小鼠通过吸入肺炎链球菌（S.肺炎），这是一种导致世界范围内许多死亡的病原体。我们已鉴定出S.我们已经证实了这些细胞的TCR依赖性活化，以在感染数小时内产生IFNγ或IL-17。虽然已经确定iNKT细胞增强肺中的先天免疫应答，但关于它们如何做到这一点以及专用于IFNγ或IL-17产生的单独iNKT细胞亚群是否表现不同的信息很少。在目标一中，我们将使用成像和其他技术来跟踪感染小鼠肺部的iNKT细胞反应。我们将确定与iNKT细胞亚群相互作用的细胞类型，它们的原位募集和扩增，以及它们的动态行为。目的二，我们将确定骨髓细胞和上皮细胞对S。在某些实施方案中，肺炎链球菌感染受iNKT细胞缺乏或iNKT细胞产生IFNγ和/或IL-17的影响。我们已经表明，IG超家族成员BTLA通过结合TNF超家族受体HVEM对上皮先天性应答是重要的。因此，同样在目的2中，我们将确定是否需要iNKT细胞表达BTLA，这将提示iNKT细胞与上皮细胞的新的直接相互作用。或者，需要另一种细胞类型表达BTLA，结合来自我们的活体成像研究的数据，将提示间接的iNKT-上皮细胞相互作用。在第三个目标中，我们将使用具有floxed Cd 1d等位基因的小鼠来鉴定必须表达CD 1d以保护性应答感染的细胞类型。我们的假设是，iNKT细胞激活肺中先天免疫的多种元素，包括上皮细胞，并且产生IFNγ和IL-17的iNKT细胞在宿主防御中具有非冗余的作用。这些研究的结果将提供有关肺中先天免疫应答以及iNKT细胞如何调节这种应答的新信息。我们将获得的对iNKT细胞功能的更多理解可能有助于改进刺激iNKT细胞对抗感染的糖脂佐剂的设计。

DESCRIPTION (provided by applicant): Invariant natural killer T cells (iNKT cells) are a fascinating, innate-like T lymphocyte population that recognizes glycolipids presented by CD1d, a class I-like antigen- presenting molecule. Mice deficient for iNKT cells are highly susceptible t infection by inhalation with Streptococcus pneumoniae (S. pneumoniae), a pathogen that is responsible for many deaths worldwide. We have identified glycolipid antigens from S. pneumoniae that activate the T cell antigen receptor (TCR) of iNKT cells, and we have shown TCR-dependent activation of these cells to produce IFNγ or IL-17 within hours of infection. While it is established that iNKT cells augment the innate immune response in the lung, there is little information as to how they do this, and if the separate iNKT cell subsets dedicated to IFNγ or IL-17 production behave differently. In aim one, we will use imaging and other technologies to track the iNKT cell response in the lung of infected mice. We will identify the cell types the subsets of iNKT cells interact with, their recruitment and expansion in situ, and their dynamic behavior. In aim two, we will determine how the innate immune response of myeloid cells and epithelial cells to S. pneumoniae is affected by the absence of iNKT cells, or iNKT cell production of IFNγ and/or IL-17. We have shown that the Ig super family member BTLA is important for epithelial innate responses by binding to the TNF super family receptor HVEM. Therefore, also in Aim 2, we will determine if BTLA expression by iNKT cells is required, which would be suggestive of a novel, direct interaction of iNKT cells with epithelial cells. Alternativey, a requirement for BTLA expression by another cell type, combined with data from our intravital imaging studies, would be suggestive of an indirect iNKT- epithelial cell interaction. In aim three we will identify the cell type(s) that must express CD1d for a protective response to infection using mice with a floxed Cd1d allele. Our hypothesis is that iNKT cells activate diverse elements of innate immunity in the lung, including epithelial cells, and that IFNγ and IL-17 producing iNKT cells have non redundant roles in host defense. The results from these studies will provide novel information on the innate immune response in the lung and how iNKT cells modulate this response. The increased understanding of iNKT cell function we will gain may contribute to the improved design of glycolipid adjuvants that stimulate iNKT cells to combat infections.