The CD8 T-cell road to immunotherapy of toxoplasmosis

Abstract

Toxoplasma gondii infection induces a robust CD8 T-cell immunity that is critical for keeping chronic infection under control. In studies using animal models, it has been demonstrated that the absence of this response can compromise the host ability to keep chronic infection under check. Therapeutic agents that facilitate the induction and maintenance of CD8 T-cell response against the pathogen need to be developed. In the last decade, major strides in understanding the development of effector and memory response, particularly in viral and tumor models, have been made. However, factors involved in the generation of effector or memory response against T. gondii infection have not been extensively investigated. This information will be invaluable in designing immunotherapeutic regimens needed for combating this intracellular pathogen that poses a severe risk for pregnant women and immunocompromised individuals.

Figure 1. CD8 T-cell effector mechanisms during acute and chronic toxoplasmosis

During the acute phase, CD8 T cells primarily via the production of IFN-γ and possibly TNF-α and cytotoxicity-associated molecules such as perforin and granzyme B inhibit parasite replication and cause conversion of the parasite from tachyzoite stage to bradyzoite stage. IFN-γ elicits the production of NO, ROS and IDO and activates p47GTPases that augment parasite clearance. During the chronic phase, CD8-produced IFN-γ and possibly TNF-α is vital for maintaining the parasites in the encysted stage. IDO: Indoleamine 2,3-deoxygenase; iNOS: Inducible nitric oxide synthetase; ROS: Reactive oxygen species.

Figure 2. Vaccination strategy targeting CD8 T-cell response against Toxoplasma

Any vaccination strategy against Toxoplasma must involve appropriate selection of adjuvant and peptide pools such that there is optimal TCR–peptide MHC interaction (signal 1), costimulation (signal 2) and cytokine milieu (signal 3) during CD8 priming. In addition to peptide pool used, adjuvant selection may need to be altered depending on whether it is a prophylactic or therapeutic vaccine. Adjuvants that are highly inflammatory will result in preferential CD8 differentiation to effector lineage that may be ideal for therapeutic vaccination. Conversely, adjuvants that elicit comparatively lower inflammation will result in robust Tcm development, which may be optimal for prophylactic vaccination regimens. APC: Antigen-presenting cell; MPEC: Memory precursor effector cell; SLEC: Short-lived effector cell; Tem: T effector memory; Tcm: Central T memory; TCR: T-cell receptor.