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

描述（由申请人提供）：不变自然杀伤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CD1d呈递的糖脂，CD1d是一类样抗原呈递分子。iNKT细胞缺乏的小鼠对吸入肺炎链球菌（S. pneumoniae）感染非常敏感，肺炎链球菌是一种导致全球许多人死亡的病原体。我们已经鉴定出肺炎链球菌的糖脂抗原，可以激活iNKT细胞的T细胞抗原受体（TCR），并且我们已经证明TCR依赖性激活这些细胞在感染后数小时内产生IFNγ或IL-17。虽然已经确定iNKT细胞增强了肺部的先天免疫反应，但关于它们是如何做到这一点的信息很少，以及用于IFNγ或IL-17产生的单独iNKT细胞亚群是否表现不同。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iNKT细胞亚群与之相互作用的细胞类型，它们的原位招募和扩增，以及它们的动态行为。在目标二中，我们将确定骨髓细胞和上皮细胞对肺炎链球菌的先天免疫反应如何受到iNKT细胞缺失或iNKT细胞产生IFNγ和/或IL-17的影响。我们已经证明，Ig超家族成员BTLA通过与TNF超家族受体HVEM结合，对上皮先天反应很重要。因此，同样在Aim 2中，我们将确定是否需要iNKT细胞表达BTLA，这将提示iNKT细胞与上皮细胞之间存在一种新的直接相互作用。或者，另一种细胞类型对BTLA表达的要求，结合我们生命成像研究的数据，可能暗示iNKT-上皮细胞之间存在间接的相互作用。在目标三中，我们将识别必须表达CD1d的细胞类型，以对带有固定CD1d等位基因的小鼠感染产生保护性反应。我们的假设是，iNKT细胞激活了包括上皮细胞在内的肺部先天免疫的多种成分，并且产生IFNγ和IL-17的iNKT细胞在宿主防御中具有非冗余作用。这些研究的结果将为肺部先天免疫反应以及iNKT细胞如何调节这种反应提供新的信息。我们将获得的对iNKT细胞功能的进一步了解可能有助于改进糖脂佐剂的设计，刺激iNKT细胞对抗感染。

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.