The mechanisms by which circulating macrophages and their liver counterparts (Kupffer and hepatic stellate cells) alter CD8+ T-cell activity

背景：*巨噬细胞等先天免疫细胞协调T细胞反应是获得性免疫的标志。巨噬细胞亚群的细胞因子的产生和细胞与细胞的接触对CD4+T细胞亚群分化的影响已经得到了很好的描述，但它们对CD8+T细胞活性和细胞溶解(CTL)功能的控制尚不清楚。血源性巨噬细胞最近被描述为M1、M2a、2b和2c亚群，建立炎症、免疫调节或组织修复细胞因子环境。此外，组织特异性巨噬细胞在维持免疫耐受、平衡CD8+T细胞渗入的免疫反应和组织破坏效应方面的作用仍有待充分描述。例如，在非酒精性脂肪性肝病中，肝脏驻留巨噬细胞(Kupffer细胞，KC和肝星状细胞，HSC)最近被描述极化为M1和M2样表型，但它们对M2a，2b或2c亚群分化的可能性尚未被研究。M1和M2亚群固有的促炎和抗炎属性可能增强或抑制CD8+T细胞活性和CTL功能。*假设：单核细胞来源的M1和M2亚群，以及同等来源的肝脏巨噬细胞亚群(库普弗细胞和肝星状细胞)，分别增强或抑制CD8+T细胞活性。*特定目标：*目的1：确定M1、M2a、M2B和M2c亚群对CD8+T细胞活性的间接和直接影响。*目标#2：确定肝巨噬细胞(Kupffer细胞)是否可以极化成M1、M2a、2b和2c样亚群，并研究它们对CD8+T细胞活性的影响。*目标#3：研究人星状细胞分化为巨噬细胞亚群的可能性，并介导CD8+T细胞活性。*相关性：*本研究将解决巨噬细胞亚群如何影响CD8+T细胞活性的根本问题。增加的一个新的组成部分是根据巨噬细胞表型和它们在适应性免疫T细胞反应中的作用来表征Kupffer细胞和肝星状细胞亚群。将先天免疫系统和获得性免疫系统与这些方法联系起来，将确定目前尚不清楚的巨噬细胞亚群和CD8+T细胞在耐受和免疫反应中的关系，特别是在肝脏中。

BACKGROUND:***The orchestration of T-cell responses by innate immune cells such as macrophages is a hallmark of adaptive immunity. The effect of cytokine production and cell-cell contact of macrophage subsets has been well described for CD4+ T-cell subset differentiation, while their control of CD8+ T-cell activity and cytolytic (CTL) function remains unclear. Blood-derived macrophages have been recently described to polarize into M1, M2a, 2b and 2c subsets, establishing inflammatory, immunoregulatory or tissue-repairing cytokine milieus. In addition, the role of tissue-specific macrophages in maintaining immune tolerance and balancing the immune response and tissue destructive effects of infiltrating CD8+ T-cells remains to be fully described. For example, liver resident macrophages (Kupffer cells, KC, and hepatic stellate cells, HSC) have recently been described to polarize to M1- and M2-like phenotypes in non-alcoholic fatty liver disease, yet their potential for M2a, 2b or 2c subset differentiation has not been investigated. The inherent pro- and anti-inflammatory attributes of M1 and M2 subsets may enhance or inhibit CD8+ T-cell activity and CTL function.***Hypothesis: Blood monocyte-derived M1 and M2 subsets, and equivalently derived subsets of liver resident macrophages (Kupffer cells and hepatic stellate cells), enhance or inhibit CD8+ T-cell activity, respectively.***SPECIFIC AIMS:***AIM #1: Identify the indirect and direct effects of M1, M2a, M2b and M2c subsets on CD8+ T-cell activity. ***AIM #2: Determine if liver macrophages (Kupffer cells) can be polarized into M1, M2a, 2b and 2c-like subsets and investigate their influence on CD8+ T-cell activity.***AIM #3: Investigate the potential of human stellate cells to be polarized into macrophage subsets and to mediate CD8+ T-cell activity.******RELEVANCE: ***This study will address the fundamental issue of how macrophage subsets influence CD8+ T-cell activity. An added novel component is the characterization of Kupffer cell and hepatic stellate cell subsets according to macrophage phenotypes and their role in adaptive immunity T-cell responses. Linking the innate and adaptive immune systems with these approaches will identify the as yet poorly understood relationship between macrophage subsets and CD8+ T-cells in tolerance and immune response, specifically in the liver.********