Latent toxoplasmosis continues to be a problem for immunocompromised infected individuals and toxoplasmic encephalitis (TE) is one of the most common life threatening central nervous system infections in these patients. The reactivation of latent toxoplasmosis is attributed to lack of adequate CD4 T cell help that compromises the CD8 T cell immunity against the parasite. Similar to humans, mouse models of toxoplasmosis have demonstrated the critical role of CD4 T cells for the maintenance of robust CD8 T cell immunity. In a recent study we demonstrated that CD8 T dysfunction leading to reactivation in chronically infected host is a consequence of CD4 T cell exhaustion. Treatment of chronic host with antigen-specific non-exhausted CD4 T cells can restore CD8 T cell functionality and prevent reactivation. Interestingly, CD4 exhaustion is linked to up-regulation of transcription factor BLIMP-1, which causes an increase in the expression of inhibitory receptors on these cells. Preliminary data for the proposal suggests that during latent toxoplasmosis increased BLIMP-1 expression leads to epigenetic changes in antigen-specific, CD4 TCM (central memory) subset. The transcription factor gains accessibility to chromatin sites on this population and changes their epigenetic landscape. BLIMP-1 ablation re-invigorates CD4 T cells due to downregulation of inhibitory receptors and increased expression of positive co-stimulatory molecules. The proposal has two specific aims.
In aim 1 we will determine the chromatin accessible sites on CD4 TCM that BLIMP-1 binds to. We plan to define the epigenetic changes in CD4 TCM during latent toxoplasmosis that leads to their exhaustion.
In aim 2 studies will be performed to evaluate if restoration of CD4 T cell function due to BLIMP-1 ablation is dependent on the up-regulation of 4-1BB and OX40 or other costimulatory molecules identified in aim 1. We will determine if cell intrinsic signaling by these co- stimulatory molecules is required for optimal recovery of CD4 T cell function in BLIMP-1 ablated cells. Finally, studies will be performed to determine if CD4 T cells treated with agonist for co-stimulatory molecules downregulate inhibitory receptors on CD8 population and confer strong effector cytotoxic program on these cells that is critical for containing chronic toxoplasma infection.
Toxoplasma gondii, an important food pathogen, causes severe economic and human toll world wide, including in the United States. The goal of this proposal is to determine the factors that allow the development and maintenance of protective immunity against the pathogen so that therapeutic agents in the susceptible hosts can be developed.
