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

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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.