M2a macrophage activation and the regulation of immune functions

巨噬细胞不同于骨髓，在免疫系统中发挥重要作用，启动先天免疫和获得性免疫。在免疫反应中，某些类型的M？调节炎症。它们在处理病毒抗原后将多肽递呈给T细胞，并分泌多种免疫介质，MF可因感染而被各种刺激激活，从而确定激活状态。目前，根据表型和功能状态，激活的MF有两种主要类型被描述为M1或M2 MF。典型的炎症性M1表型是由脂多糖和干扰素诱导的，而M2表型是在细胞因子IL-4的刺激下发展起来的。根据M2MF的基因表达谱，进一步将其细分为三个不同的亚型(M2a、b和c)。M2a亚型在针对寄生虫等寄生虫感染的Th2免疫反应中发挥作用。科学问题：对感染的免疫力很大程度上取决于1型和2型细胞因子的平衡。在病毒感染中，干扰素？免疫调节已经得到了很好的研究，然而，关于2型(如IL-4)免疫反应如何调节CD8+T细胞功能的研究还很少。IL-4会以一种特定的方式激活MF，与干扰素-β诱导的方式不同。激活，这不应被混淆为IL-4诱导的MF失活。我们的目标：描述M2aMF是如何调节CD8+T细胞功能的，以及在病毒感染后这会转化为什么类型的免疫。基本原理：我们最近发表的数据表明，与目前的教条相反，M2a极化的MF可以通过抗原提呈刺激而不是抑制表位特异性CD8+T细胞，从而有效地产生干扰素-α；这是抗病毒免疫反应的一个重要特征。然而，这些M2a极化的MF并没有刺激CD8+T细胞的强劲扩张。因此，我们假设在存在IL-4的情况下，M2a MF将复杂地调节病毒感染期间的CD8+T细胞功能。在这项提案中，我们将解决以下目标：目标1确定M2a MF如何对病毒感染做出反应。目的研究上述模型中影响CD8+T细胞功能的转录因子。目的#3研究IL-4存在时对病毒感染的免疫力。总体而言，这一长期项目与我们在这一研究领域的广泛专业知识非常吻合。此外，这里描述的研究应该确定新的科学知识，以帮助我们了解在病毒-免疫系统相互作用过程中，某些细胞因子激活MF如何影响多个免疫参数。

Macrophages (Mf) differentiate from the bone marrow and perform important functions within the immune system to initiate both innate and adaptive immunity. During an immune response, certain types of M? regulate inflammation. They present peptides to T-cells after processing viral antigens and secrete a variety of immune mediators Mf can be activated by a variety of stimuli because of infections, which can determine the activation status. Currently, two main types of activated Mf have been described as M1 or M2 Mf, based on their phenotypic and functional status. The pro-inflammatory M1 phenotype is classically induced by lipopolysaccharide (LPS) and interferon-gamma (IFN?), whereas M2 Mf, develop during stimulation with the cytokine IL-4. The M2 Mf have been further subdivided into three different subtypes (M2a, b, and c) based on their gene expression profiles. The M2a subtypes play a role in Th2 immune responses against parasitic infections such as helminths. Scientific problem: Immunity to infections is strongly determined by the balance of type 1 vs type 2 cytokines. In viral infection, IFN-? regulation of immunity has been well-studied, yet, little is known about how type 2 (e.g. IL-4) immune responses regulate CD8+ T cell functions. IL-4 will activate Mf in a specific way, divergent from that is induced by IFN-? activation, which should not to be confused as an IL-4-induced deactivation of Mf. Our goal: To delineate how the M2a Mf are regulating CD8+ T cell functions and what type of immunity does this translates into after virus infection. Rationale: Our recently published data indicate that, contrary to the present dogma, M2a polarized Mf can stimulate rather than suppress epitope specific CD8+ T cells through antigen presentation to efficiently produce IFN-?; an important feature of the anti-viral immune responses. However, these M2a polarized Mf did not stimulate robust expansion of the CD8+ T cells. We therefore, hypothesize that in the presence of IL-4, M2a Mf will intricately regulate CD8+ T cell functions during viral infections. In this proposal, we will address the following aims: Aim#1 Determine how M2a Mf respond to virus infection. Aim#2 Determine the transcription factors influencing CD8+ T cell functions in the above model. Aim#3 Investigate immunity to virus infection in the presence of IL-4. Overall, this long-term project fits nicely with our extensive expertise in this research area. Moreover, the studies described here should identify novel scientific knowledge to help us understand how Mf activation with certain cytokines can influence multi-immune parameters during virus-immune system interactions.