The PD-1 pathway and NKT cell activation

描述(申请人提供)：NKT细胞同时表达一种独特的T细胞受体和NK标记，并可根据其细胞因子谱和激活标记进行细分。NKT细胞在抗感染病原体、肿瘤免疫监测、自身免疫诱导和控制等方面具有重要作用。众所周知，糖脂α-半乳糖基神经酰胺(α-GalCer)是由抗原提呈细胞上的CD1d分子提呈的，能有效激活NKT细胞。然而，共刺激在NKT细胞抗原特异性激活中的研究还处于起步阶段。NKT细胞表达CD28，阻断CD28通路可导致刺激后干扰素-γ和IL-4水平下降。这些结果证实了正向共刺激分子在NKT细胞激活中的作用。近年来，T细胞共刺激家族成员的数量有所增加，有的具有正功能，有的具有负功能。负共刺激分子如PD-1通路在NKT细胞功能中的作用尚未被研究。初步资料表明，NKT细胞表达PD-1和PD-L1，推测PD-1通路参与负调控NKT细胞。这一假说提出了几个将在本项目中解决的关键问题：1)PD-1配体在抑制NKT功能方面是否具有独特或重叠的作用；2)树突状细胞或其他细胞类型是NKT细胞下调反应的焦点？3)阻断NKT细胞上的PD-1途径是否会导致耐受性下降。因此，在目的1中，我们将检测PD-L1缺陷小鼠和PD-1转基因小鼠NKT细胞的发育和功能。在目标2中，我们将研究缺乏PD-1配体的树突状细胞和NKT细胞之间的相互作用。在小鼠抗肿瘤模型中，α-GalCer成功地激活了NKT细胞，导致了α-GalCer在晚期实体瘤患者中的1期研究。我们的研究将对PD-1相互作用在NKT细胞抑制效应中的作用提供关键的见解，并可能为肿瘤免疫、自身免疫和移植的治疗干预提供重要的靶点。

DESCRIPTION (provided by applicant): NKT cells express both a unique T cell receptor and NK marker and may be subdivided according to their cytokine profile and activation markers. NKT cells have been demonstrated to be important in the protection against infectious pathogens, immune surveillance of tumors and induction and control of autoimmunity. It is well known that the glycolipid alpha-galactosylceramide (alpha-GalCer) is presented by CD1d molecules on antigen presenting cells and potently activate NKT cells. However, the study of costimulation in antigen specific activation of NKT cells is still in its infancy. NKT cells express CD28 and blockade of this pathway leads to a decrease in IFN-gamma and IL-4 after stimulation. These results demonstrate the role of a positive costimulator in the activation of NKT cells. Recently, the number of T cell costimulatory family members has increased with some having positive or negative functions. The role of the negative costimulatory molecules such as the PD-1 pathway in NKT cell function has not been investigated. Preliminarily data shows that NKT cells express PD-1 and PD-L1 and leads us to hypothesize that the PD-1 pathway is involved in negatively regulating NKT cells. This hypothesis raises several key questions that will be addressed in this project 1) Do the PD-1 ligands have unique or overlapping roles in inhibiting NKT function 2) Are dendritic cells or another cell type the focus of the downregulating response of NKT cells? 3) Does blockade of the PD-1 pathway on NKT cells lead to a breakdown in tolerance. Therefore, in Aim 1 the development and function of NKT cells in PD-L1 deficient mice and PD-1 transgenic mice will be examined. In Aim 2, we will investigate the cross talk between dendritic cells and NKT cells lacking the PD-1 ligands. The success of the activation of NKT cells with alpha-GalCer in murine anti-tumor model has lead to a phase 1 study with a-GalCer in advanced patients with solid tumors. Our studies will give key insights into the role of PD-1 interactions in the inhibitory effects of NKT cells and may provide important targets for therapeutic interventions in tumor immunity, autoimmunity and transplantation.