The Diverse Role of NK Cells in Immunity to Toxoplasma gondii Infection

The obligate intracellular parasite Toxoplasma gondii (T. gondii), found in ~30% of humans worldwide, is a significant health risk for people with HIV/AIDS, people undergoing chemotherapy treatment or organ transplantation, and for developing fetuses as a result of congenital infection [1]. Infection can cause death, blindness, spontaneous abortion, or mental retardation and is correlated with behavior and neurocognitive changes [2]. No therapies exist to prevent or clear parasite infection, which is lifelong. CD8 T cell interferon (IFN)γ is the major mechanism of protection [3,4]; however, many immune factors contribute to successful parasite control. One is the natural killer cell (NK cell) [5]. NK cells are considered group 1 innate lymphoid cells (ILCs) and provide defense against tumors and intracellular pathogens (viruses, bacteria, and parasites) [6]. They use surface receptors (activating, inhibitory, and cytokine) to survey host cells and tissues for damage or infection. Receptor engagement stimulates killing of diseased target cells (cytotoxicity) and initiating IFNγ production. Activating receptors recognize specific ligands expressed on target cell surfaces and activate via cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAM) or associated adapter molecules DAP10 and DAP12 [7]. Inhibitory receptors inhibit by assessing self through MHC Class I (MHCI) recognition and, when triggered, recruit ITAM-antagonizing phosphatases SHIP1 and SHP1 via cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM) [8]. Inflammatory cytokines IFNα/β, Interleukin (IL)-2, IL-12, IL-15, and IL-18 synergize with activating receptor signals or stimulate NK cell activation alone [7]. Other functional surface proteins include FcγRs, Fas, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Ultimately, these surface proteins regulate NK cell function depending upon the stimulatory environment. Studies of NK cell responses to T. gondii have broadly impacted parasite immunology and NK cell fields. Thus, T. gondii is an excellent and relevant model to investigate NK cell biology. This model will be important in future studies, given newly emerging NK cell adaptive immune and regulatory roles and their therapeutic potential.