M2a macrophage activation and the regulation of immune functions

M2a巨噬细胞的激活与免疫功能的调节

• 批准号: RGPIN-2021-03093
• 负责人: Basta, Sameh
• 金额: $ 2.33万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746081
• 关键词: M2a; macrophage; activation; regulation; immune

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.

巨噬细胞（Mf）从骨髓分化出来，在免疫系统中发挥重要作用，启动先天性和适应性免疫。在免疫反应期间，某些类型的M？调节炎症。它们在处理病毒抗原后将多肽呈递给T细胞，并分泌多种免疫介质Mf，Mf可因感染而被多种刺激物激活，这可决定其激活状态。目前，两种主要类型的活化Mf已被描述为M1或M2 Mf，基于它们的表型和功能状态。促炎M1表型通常由脂多糖（LPS）和干扰素-γ（IFN？）诱导，而M2 Mf在细胞因子IL-4刺激期间产生。M2 Mf根据其基因表达谱进一步细分为三种不同亚型（M2 a、B和c）。M2 a亚型在针对寄生虫感染如蠕虫的Th 2免疫应答中发挥作用。科学问题：对感染的免疫力主要由1型与2型细胞因子的平衡决定。在病毒感染，干扰素-？免疫的调节已经被充分研究，然而，关于2型（例如IL-4）免疫应答如何调节CD 8 + T细胞功能知之甚少。IL-4将以一种特定的方式激活Mf，与IFN-γ诱导的方式不同。激活，这不应被混淆为IL-4诱导的Mf失活。我们的目标是：描述M2 a Mf如何调节CD 8 + T细胞功能，以及在病毒感染后这种功能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，M2 a极化的Mf可以通过抗原呈递刺激而不是抑制表位特异性CD 8 + T细胞，以有效地产生IFN-γ;抗病毒免疫反应的一个重要特征。然而，这些M2 a极化的Mf不刺激CD 8 + T细胞的稳健扩增。因此，我们假设在IL-4的存在下，M2 a Mf将在病毒感染期间复杂地调节CD 8 + T细胞功能。在本提案中，我们将解决以下目标：目标#1确定M2 a Mf如何响应病毒感染。目的#2确定在上述模型中影响CD 8 + T细胞功能的转录因子。目的#3研究在IL-4存在下对病毒感染的免疫力。总体而言，这个长期项目非常符合我们在该研究领域的广泛专业知识。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-免疫系统相互作用期间，Mf与某些细胞因子的激活如何影响多免疫参数。