Ocular toxoplasmosis, which is caused by infections with the protozoan parasite Toxoplasma gondii, is the most common form of infectious retinitis. The disease is caused when quiescent Toxoplasma tissue cysts reactivate in the retina and a properly regulated immune response is not mounted. One component of this regulation is controlling infiltrating CD4 T-cells. But, how these T-cells are regulated in Toxoplasma infected retinas is unknown. Our hypothesis is that retinal expression of MHC Class II and the negative costimulatory molecule PD-L1 (also known as B7H1) are important in regulating the T-cells. In support of this hypothesis, we have discovered that MHC Class II and PD-L1 are expressed in the infected retina on both infiltrating leukocytes as well as resident neural retinal cells. Class II and PD-L1 were functionally expressed since cells from parasite-infected retinas could suppress T-cell recall responses to Toxoplasma antigen. Finally, loss of PD-L1 leads to significant retinal damage in Toxoplasma-infected animals. To further test our hypothesis, three specific aims are proposed.
Specific Aim #1 will determine where in the eye the T-cell suppressive activity is localized.
Specific Aim #2 will define the consequence of ocular PD-L1 expressing cells on T-cells.
In Specific Aim #3, we will determine whether resident retinal cells can act at negative-regulators of activated T-cells. These studies will provide critical information regarding retinal immune privilege in Toxoplasma infections as well as other immune-based retinal diseases.
The goal of this application is to understand how the immune system is regulated when it responds to infections in the eye with the protozoan parasite Toxoplasma gondii from causing retinal disease. Understanding these mechanisms is important for the development of new treatments for this potentially blinding disease.
| Butler, Noah S; Harris, Tajie H; Blader, Ira J (2013) Regulation of immunopathogenesis during Plasmodium and Toxoplasma infections: more parallels than distinctions? Trends Parasitol 29:593-602 |
