MONONUCLEAR PHAGOCYTES: CRITICAL PLAYERS IN BOTH MAINTAINING TISSUE HOMEOSTASIS AND INITIATING AND POTENTIATING THE ADAPTIVE IMMUNE RESPONSE
Open Access
- Author:
- Granger, Erica Lynn
- Graduate Program:
- Microbiology and Immunology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 24, 2010
- Committee Members:
- Christopher Charles Norbury, Dissertation Advisor/Co-Advisor
Christopher Charles Norbury, Committee Chair/Co-Chair
Sarah Bronson, Committee Member
Thomas Wright Gardner, Committee Member
Todd Schell, Committee Member
David Joseph Spector, Committee Member - Keywords:
- dendritic cell
antigen presentation
microglia
diabetic retinopathy - Abstract:
- Macrophages and dendritic cells (DC) belong to the mononuclear phagocyte system (MPS) and are vital immune cells found in every organ of the body. They are critical in tissue generation and homeostasis as well as for initiating innate and adaptive immune responses. The importance of these cells is exemplified by the inability of mice to survive in the absence of both DC and macrophages. The role of mononuclear phagocyte migration, particularly DC migration, to initiate an immune response to a peripheral virus infection was previously unclear. We examined the generation of antigen-specific CD8+ T cells (TCD8+) after immunization with recombinant adenoviruses (rAd) that express antigen driven by skin-specific or ubiquitous promoters. Following immunization with rAd expressing antigen only in the skin, DC show a brief migratory burst, lasting approximately 1-2 days. This lack of sustained DC migration limits the effector TCD8+ response, preventing the complete killing of peptide pulsed cells. This is the first time a functional consequence is shown due to a lack of DC migration. DC, in addition to being critical players in initiating the immune response to a peripheral virus infection, are also critical in extending antigen presentation to TCD8+ for 40+ days following immunization with recombinant vaccinia virus (rVACV). The persistence of antigen presentation consists of 3 distinct phases. The first phase of antigen presentation persistence encompasses 12-14 days of ongoing virus replication. The second phase, which is approximately 2 weeks, reflects the lifespan of virally infected cells. The third stage requires cross presentation of antigen by DC, extending antigen presentation for approximately 18 additional days. Microglia, the tissue resident macrophage of the central nervous system (CNS) are critical mononuclear phagocytes that are important in maintaining tissue homeostasis. Interestingly, we show that microglia isolated from the retina and brain are different and one cannot be substituted for the other. The role of retinal microglia during an inflammatory disease of the retina, diabetic retinopathy (DR), remained elusive until now. In various diabetic mouse models a subset of microglia in the retina, but not in the brain, becomes activated at a late stage of diabetes (3+ months) in the absence of IL-1. These activated microglia produce reactive oxygen species (ROS) and produce less TNFα in response to LPS stimulation in vivo, suggesting an alternative activation state. Our findings have important implications in rational vaccine design and treatment of chronic inflammatory diseases. Promoting DC migration and using long-lived protein that can be cross-presented may initiate a more robust TCD8+ response yielding a more effective vaccine. Additionally, understanding the role of microglia during DR may ideally lead to the identification of potential therapeutic targets. Together, these experiments have demonstrated the importance of mononuclear phagocytes in both tissue homeostasis and in the immune response to viral infections.