M2a macrophage activation and the regulation of immune functions

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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.