Functional Roles of NKp46 in Transplantation

描述（由申请人提供）：自然杀伤（NK）细胞是先天免疫系统的效应细胞，可在不事先致敏的情况下裂解靶细胞，并在宿主防御病原体和转化细胞中发挥重要作用。NK细胞功能由通过生殖系编码的抑制性和激活性受体传递的负信号和正信号的平衡控制。虽然“缺失自我”的概念表明NK细胞可以靶向异体移植物，但普遍的教条是NK细胞不是导致移植物排斥的机制的积极参与者。然而，最近的研究挑战了这一结论，而是将NK细胞与急性和慢性同种异体移植排斥反应联系起来。相当矛盾的是，NK细胞也被证明有助于对同种异体移植物的耐受。为了调和这些不同的观察结果，我们假设NK细胞通过活化受体的表达和功能调节免疫系统的其他细胞，特别是树突状细胞（DC）。事实上，我们已经证明，DC介导的NK细胞活化依赖于通过NKp 46活化受体的信号传导。这一探索性/发展性建议的目标是确定NK相互作用如何调节移植后的适应性免疫应答。我们提出了两个综合的具体目标：1）确定移植后NK细胞的表型和功能特征，2）确定NKp 46如何促进移植后NK细胞的功能，以验证我们的假设，即NKp 46在调节移植后NK介导的免疫功能中很重要。我们的创新性研究将对设计预防移植排斥反应和促进同种异体移植耐受的策略具有重要意义。

DESCRIPTION (provided by applicant): Natural killer (NK) cells are effector cells of the innate immune system that can lyse target cells without prior sensitization, and have an important role in host defense to pathogens and transformed cells. NK cell function is controlled by a balance of negative and positive signals transmitted via germ-line encoded inhibitory and activating receptors. Although the concept of "missing-self" would suggest NK cells could target foreign allografts, the prevailing dogma has been that NK cells are not active participants in the mechanisms that culminate in graft rejection. Recent studies, however, challenge this conclusion and instead implicate NK cells in both acute and chronic allograft rejection. Quite paradoxically, NK cells have also been shown to facilitate tolerance to an allograft. To reconcile these disparate observations we hypothesized that NK cells, through expression and function of activating receptors, regulate other cells of the immune system especially dendritic cells (DC). Indeed we have demonstrated that DC- mediated activation of NK cells is dependent upon signaling through the NKp46 activation receptor. The goal of this exploratory/developmental proposal is to determine how NK interactions regulate the adaptive immune response after transplantation. We propose two integrated Specific Aims: 1) determine the phenotypic and functional features of NK cells after transplantation and 2) determine how NKp46 contributes to the function of NK cells post-transplant, to test our hypothesis that NKp46 is important in regulating NK-mediated immune functions post-transplant. Our innovative study will have important implications in designing strategies to prevent graft rejection and promote tolerance to an allograft.