The role of c-Rel in protective immunity to Toxoplasma gondii infection

Many infectious and inflammatory stimuli lead to the activation of the Rel/NF-κB family of transcription factors which play an important role in the development of innate and adaptive immune responses. As part of the NF-κB family, c-Rel is expressed predominantly in immune cells and regulates the expression of many genes that are involved in the initiation of the innate and adaptive immune response. However, the role of and requirement for c-Rel in specific cell types during a coordinated immune response to infection is unknown. The aim of this thesis was to investigate the role of c-Rel during the immune response to infection with the intracellular parasite, Toxoplasma gondii, which causes significant morbidity and mortality in immunocompromised patients. The immune response to T. gondii is well characterized and provides a useful tool for investigating the role of immune molecules during infection. The studies presented here reveal that although c-Rel is essential for the production of IL-12 in response to many infectious and inflammatory stimuli, it is dispensable for the production of IL-12 during infection with T. gondii. Further investigations into mechanisms of IL-12 production in response to toxoplasma have revealed a TRAF6-p38MAPK dependent pathway that supports suggestions that this parasite may signal through TLR pathways. The studies presented here reveal that although c-Rel is not required for the generation of Th1 effector cells in response to infection, T cell intrinsic expression of c-Rel is required for the optimal activation and expansion of Th1 effector cells and resistance to T. gondii. Moreover, antigen-presenting and costimulatory defects in c-Rel−/− dendritic cells are likely to contribute to suboptimal Th1 effector cell development. Finally, the results reported here suggest that c-Rel is required for the generation and/or maintenance of effector memory cells and long-term protective immunity during toxoplasmosis. Taken together, these studies indicate that c-Rel is an important regulator of innate immune responses and acts to optimize and maintain adaptive T cell responses during infection. Thus, these studies identify and further define functions of c-Rel that are distinct, specific and non-overlapping with other NF-κB family members during infection