Post-thymic Thpok-deficiency in CD4 T cells compromises control of Toxoplasma gondii infection

Abstract

Abstract Toxoplasma gondii, an intracellular parasite, is estimated to chronically infect >25% of the world-wide human population. While generally kept in check by the host immune system, reactivation of infection can occur when individuals become immunocompromised, particularly with T cell deficiencies. Both CD4+ and CD8+ T cells play significant roles in controlling this parasite. The transcription factor Thpok, is critical for commitment of MHC Class II-restricted thymocytes to the CD4 lineage during thymic differentiation, but also plays a significant post-thymic role in shaping the effector function of mature CD4+ T cells. Based on these findings, we interrogated how mice with post-thymic deletion of Thpok manage a chronic infection using Toxoplasma gondii (“Toxo” hereafter). During acute infection, Thpok-deficient mice have equivalent expansion of Toxo-specific T cells compared to WT littermate controls, but these CD4 T cells have undergone “cytotoxic diversion”, upregulation of a CD8 transcriptional program and loss of CD4 helper function. During the chronic phase of infection Thpok-deficient mice die (~3 weeks p.i. vs >12 weeks for WT) and exhibit increased Toxo cysts in the brain compared to WT littermates, suggesting deficient control of the parasite. This death in the early chronic phase is not simply due to lack of CD4+ T cell help, as Class II-deficient mice survive significantly longer into the chronic phase of Toxo infection (~6 weeks, p.i.). This data indicates that Thpok-deficient CD4+ T cells are far worse at controlling Toxo than complete absence of CD4+ T cells. Studies are currently in progress to address the mechanism by which Thpok-deficiency dysregulates parasite control by CD4+ T cells. Intramural National Institutes of Health