Figure 2. Immune response to protozoan parasites and development of T cell exhaustion.

Protozoan parasites evoke a strong immune response which begins with their encounter with a potent antigen presenting population such as dendritic cells (DC). This leads to DC activation which is manifested by strong IL-12 production and expression of multiple co-stimulatory molecules (CD80/86, CD40/40L, etc.) on the surface. Subsequently, the antigen is processed and the resulting peptides are presented to T cells in the context of MHC molecules, leading to their activation, clonal expansion and differentiation into an effector population. Due to their ability to exhibit polyfunctional ability (cytotoxic activity and production of inflammatory cytokines such as IL-2, TNFα and IFNγ) the effector T cells (both CD4 and CD8 T cell subset) are able to resolve the acute infection, and a memory response against the pathogen is developed, which is highly efficient in controlling re-infection with the same pathogen. However, in the case of parasites which lead to chronic infection, the presence of high antigenic load causes T cells to express inhibitory molecules such as PD-1 in a graded manner, resulting in loss of their polyfunctional ability with a concomitant increase in apoptotic potential (bottom panel). The dysfunctional or exhausted T cells are unable to clear the parasites and in severe cases undergo deletion.