miR146a and CD4 dysfunction during chronic toxoplasmosis

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Toxoplasmic gondii, an apicomplexan parasite is a pathogenic protozoan that can infect the central nervous system. Infection during pregnancy can result in congenital infection with severe neurological consequences. In immunocompromised individuals reactivation of latent neurological foci can result in encephalitis. Although CD8+ T cells play an important effector role in controlling the chronic infection, their maintenance is dependent on critical help provided by CD4 T cells. In a very 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. In this proposal mechanism responsible for CD4 T cell dysfunction/exhaustion during chronic toxoplasmosis will be interrogated. Preliminary data for the proposal suggests that increased expression of transcription factor BLIMP-1 on CD4 T cells is due to up-regulation of miR146a, which likely is a primary cause of their dysfunction. The proposal has two specific aims. In aim 1 the mechanism responsible for increased BLIMP-1 expression on CD4 T cells will be evaluated. As preliminary data points at the role of miR146a, the studies will be performed to determine if in the absence of miR146a, BLIMP-1 expression can be down-regulated and CD4 T cell exhaustion prevented. Experiments will be performed to determine if over-expression of miR146a on non-exhausted CD4 T cells can lead to their dysfunctionality. Preliminary data for the proposal shows that antigen-specific CD4 T cells from miR146-/- mice express increased TRAF6 as compared to the cells from wild type animals. In aim 2, studies related to novel concept that TRAF6 plays an important role in the regulation of BLIMP-1 on CD4 T cells will be performed. We plan to determine if increased BLIMP-1 expression on CD4 T cells (due to targeting of TRAF6 by miR146a) alters their metabolic pathway.