Cd1d regulation and its effect on NKT cell activation

描述（由申请人提供）：NKT细胞是独特的T细胞，与NK细胞具有某些共同特性，并识别由CD1d呈递的脂质抗原。CD1d和NKT细胞在人类和小鼠之间是进化保守的，并且鼠模型提供了对CD1d和CD1d限制性T细胞的生物学的相当深入的了解。根据模型，NKT细胞促进或抑制与自身免疫性疾病相关的组织炎症。CD1d限制性NKT细胞也对宿主免疫力做出重要贡献，以对抗许多不同的病原体，包括寄生虫，真菌，病毒和细菌。NKT细胞识别的抗原是未知的。越来越多地，似乎CD1d提出自身脂质抗原。如果内源性配体激活NKT细胞，则必须调节CD1d的抗原呈递以防止NKT细胞的不适当激活。这项研究的重点是确定APC上CD1d的表达是如何调节的，以及其调节是否会影响CD1d限制性免疫反应。虽然对CD1d的调控知之甚少，但我们观察到细胞因子和微生物制品协同诱导CD1d表达。正如I类和II类MHC分子的上调促进MHC限制性免疫应答一样，CD1d的上调可能促进NKT细胞活化。我们假设感染后，通过Toll样受体（TLR）和IFNgamma受体的信号传导导致APC上CD 1d的细胞表面表达增加。这反过来又会促进CD1d限制性NKT细胞的活化，这些细胞在受到刺激时具有抗菌和免疫调节特性。这项资助将确定细胞表面CD1d水平是否调节原代NKT细胞的活化。我们将继续确定组织炎症是否在体内诱导CD1d，以及CD1d水平是否影响体内NKT细胞的活化。最后，我们将确定细胞因子和微生物产物如何产生细胞内信号，导致CD1d上调，以及如何在分子水平上调节CD1d的表达。了解CD1是如何调节的，以及NKT细胞在感染后如何被激活，将澄清NKT细胞在对人类病原体的免疫中的作用，并提供对它们在其他免疫反应中的生理作用的见解。

DESCRIPTION (provided by applicant): NKT cells are unique T cells that share some properties with NK cells and recognize lipid antigens presented by CD1d. CD1d and NKT cells are evolutionary conserved between humans and mice, and the murine model has provided considerable insight into the biology of CD1d and CD1d- restricted T cells. Depending on the model, NKT cells either contribute to, or suppress, tissue inflammation associated with autoimmune disease. CD1d-restricted NKT cells also make a critical contribution to host immunity against many diverse pathogens, including parasites, fungi, viruses and bacteria. What antigens NKT cells recognize is unknown. Increasingly, it appears that CD1d presents self-lipid antigens. If endogenous ligands activate NKT cells, then antigen presentation by CD1d must be regulated to prevent inappropriate activation of NKT cells. The focus of this grant is to determine how CD1d expression on APC is regulated and whether its modulation influences CDId-restricted immune responses. Although little is known about CD1d regulation, we have observed that cytokines and microbial products synergize to induce CD1d expression. Just as upregulation of class I and II MHC molecules promote MHC-restricted immune responses, upregulation of CD1d may promote NKT cell activation. We hypothesize that following infection, signaling through Toll-like Receptors (TLR) and the IFNgamma-receptor leads to increased cell surface expression of CD1d on APC. This will in turn promote activation of CD1d-restricted NKT cells, which when stimulated, have antimicrobial and immunoregulatory properties. This grant will determine whether cell surface CD1d levels modulate the activation of primary NKT cells. We will go on to determine whether tissue inflammation induces CD1d in vivo, and whether CD1d levels affect the activation of NKT cells in vivo. Finally we will determine how cytokines and microbial products generate an intracellular signal to cause CD1d upregulation, and how the CD1d expression is regulated at the molecular level. Understanding how CD1 is regulated and how NKT cells become activated following infection will clarify the role of NKT cells in immunity to human pathogens, as well as provide insight into their physiological role in other immune responses.