Toxoplasma gondii is a major opportunistic parasitic infectious agent in man and animals. Disease can result from a weak immune response resulting in parasite lysis of host tissue or it can ensue from an inappropriate or overly exuberant immune reaction. The major protective immune mechanism against T. gondii and other intracellular pathogens is that mediated by T helper 1 (Th1) cells, which produce pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Nevertheless, when produced in excess, these protective cytokines can become pathologic. How Th1 cells are self-regulated has not been well understood. Our work from the previous funding period has unraveled a key negative control loop in Th1 responses whereby IFN-gamma induces the production of the anti-inflammatory cytokine IL-10, Th1 cells themselves. Therefore, the current application will determine how IL-10 is regulated and functions to protect the host from self-inflicted immune-injury.
Our first aim i s to determine what signals and cells program the Th1 cells to produce IL-10 in the first place. Secondly, we will investigate the role of specialized innate cells in driving the differentiation of Th1 cells producing IL-10. Finally, we will elucidate the cytokine and cellular components of the negative feedback loop whereby IFN-gamma induces reactivation of IL-10 in Th1 memory cells. These studies will identify key mechanisms used by the immune system to simultaneously clear microbial pathogens but also prevent host tissue damage.
Human diseases caused parasitic protozoa and other types of intracellular pathogens are major causes of human mortality and morbidity globally. Disease may be caused by tissue destruction by parasites or result from an over-reaction by the immune response. The studies proposed here will advance understanding of how the Th1 response can provide protection against parasites and other pathogens but also prevent or avert collateral tissue damage. Insights obtained from this research will hopefully be useful for management strategies and treatment for chronic infectious diseases.
|Wilson, Douglas C; Matthews, Suzanne; Yap, George S (2008) IL-12 signaling drives CD8+ T cell IFN-gamma production and differentiation of KLRG1+ effector subpopulations during Toxoplasma gondii Infection. J Immunol 180:5935-45|
|Zhao, Yanlin; Wilson, Douglas; Matthews, Suzanne et al. (2007) Rapid elimination of Toxoplasma gondii by gamma interferon-primed mouse macrophages is independent of CD40 signaling. Infect Immun 75:4799-803|
|Gaddi, Pamela J; Yap, George S (2007) Cytokine regulation of immunopathology in toxoplasmosis. Immunol Cell Biol 85:155-9|
|Shaw, Michael H; Freeman, Gordon J; Scott, Mark F et al. (2006) Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-gamma-dependent IL-10 reactivation. J Immunol 176:7263-71|
|Ling, Yun M; Shaw, Michael H; Ayala, Carol et al. (2006) Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. J Exp Med 203:2063-71|
|Yap, George S; Shaw, Michael H; Ling, Yun et al. (2006) Genetic analysis of host resistance to intracellular pathogens: lessons from studies of Toxoplasma gondii infection. Microbes Infect 8:1174-8|
|Shaw, Michael H; Boyartchuk, Victor; Wong, Sandy et al. (2003) A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity. Proc Natl Acad Sci U S A 100:11594-9|
|Yap, George S; Sher, Alan (2002) The use of germ line-mutated mice in understanding host-pathogen interactions. Cell Microbiol 4:627-34|