PD-1 signaling impacts T cell function during the early phase of infection with Toxoplasma gondii

Abstract Long term resistance to T. gondii is mediated via T cell production of IFN-γ, but during chronic infection CD8+ T cells show signs of reduced capacity to secrete IFN-γ associated with increased expression of multiple inhibitory receptors. Blockade of the inhibitory receptor ligand PD-L1 during the chronic phase of infection has been reported to increase the functionality of CD8+ T cell responses and result in reduced parasite burden. However, the impact of PD-1 signaling on the immune response to T. gondii during the early phase of infection is unknown. PD-L1 blockade during the acute phase of toxoplasmosis resulted in an increased proportion of activated CD8+ T cells (CD69+, LFA-1hi) accompanied by an increased proportion of polyfunctional CD8+ T cells (IFN-γ+, Granzyme B+). This effect did not result in increased immune pathology or reduce parasite burden. Unexpectedly, this intervention resulted in a significant increase in the expression of inhibitory receptors such as PD-1, TIM3, and CTLA-4 on the long-lived T-intermediate (Tint, CXCR3+/KLRG1+) CD8+ T cell population, while increasing the proportion of terminally differentiated T cells in specific sites of infection. These datasets suggest PD-1 signaling in the early phase of T. gondii infection constrains CD8+ T cell effector differentiation and may act to preserve pathogen specific Tint subsets that are needed for long term resistance to this persistent infection.