HREM image of mouse head during development

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Cellular and molecular activation of macrophages during infection and allergy

Project supervisor – Mark Wilson

Division of Molecular Immunology

The mobilization and activation of a variety of innate cells, especially macrophages, by effector T helper 2 (Th2) cells is an important mechanism for anti-helminth immunity [Anthony, 2006; Okoye, 2011]. Using genome-wide analysis of intestinal tissue from helminth-resistant hosts, compared to helminth-susceptible host, we have identified a suite of up-regulated genes associated with macrophage activation. During chronic airway inflammation, as seen in allergic asthma, alveolar macrophages are both early responders to airborne allergens and also become alternatively activated by Th2-cytokines, such as Interleukin-4 (IL-4) and IL-13 [Balhara, 2012]. Thus, macrophages have the capacity to both shape the development and downstream responses following allergen exposure or helminth infection.

Surprisingly, the molecular pathways involved in physiological activated macrophages by T cells are poorly understood. The conventional in-vitro method of macrophage activation, used to model these complex interactions, is with LPS and IFNγ for classical activation, IL-4 and IL-13 for alternative activation and IL-10 for regulatory macrophage activation [Wynn, 2011; Zhang, 2008]. How relevant these reductionist systems are to physiological T cell activated macrophages, or to natural macrophage activation in-vivo, is unclear.

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To investigate the interaction of T cells and macrophages, we have developed a 2-cell co-culture system using primary T cells isolated ex-vivo from various sources to identify the specific cellular and molecular events during macrophage activation by T cells. Using this system, we aim to 1) Identify the phenotype of macrophages activated by a variety of T cells isolated from allergic or infected hosts and compare these macrophages to the well-studied classical, alternative and regulatory activated macrophages or to macrophages isolated ex-vivo; 2) Identify the requirements of specific intracellular kinases during T cell-mediated or conventional macrophage activation. Collectively, these studies will identify the phenotype of T cell-activated macrophages and the requirement for specific intracellular signaling pathways.

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