The PD-1 pathway and NKT cell activation

描述（由申请人提供）：NKT细胞表达一种独特的T细胞受体和NK标记物，并可根据其细胞因子谱和激活标记物进行细分。NKT细胞已被证明在抵抗感染性病原体、肿瘤免疫监测以及诱导和控制自身免疫方面具有重要作用。众所周知，糖脂α -半乳糖神经酰胺（α - galcer）由CD1d分子呈递到抗原呈递细胞上，并能有效激活NKT细胞。然而，共刺激对NKT细胞抗原特异性活化的研究仍处于起步阶段。NKT细胞表达CD28，阻断该通路导致刺激后ifn - γ和IL-4的减少。这些结果证明了阳性共刺激剂在NKT细胞活化中的作用。近年来，T细胞共刺激家族成员的数量有所增加，其中一些具有正功能或负功能。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。初步数据显示NKT细胞表达PD-1和PD-L1，我们推测PD-1通路参与了NKT细胞的负调控。这一假设提出了本项目将解决的几个关键问题1)PD-1配体在抑制NKT功能中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通路是否会导致耐受性的破坏？因此，在Aim 1中，我们将研究NKT细胞在PD-L1缺陷小鼠和PD-1转基因小鼠中的发育和功能。在Aim 2中，我们将研究缺乏PD-1配体的树突状细胞和NKT细胞之间的串扰。α - galcer在小鼠抗肿瘤模型中激活NKT细胞的成功，导致了a- galcer在晚期实体瘤患者中的一期研究。我们的研究将为PD-1相互作用在NKT细胞抑制作用中的作用提供关键见解，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.