Insights on the mechanisms of the protective immunity in the brain from the studies on infection with an intracellular microorganism, Toxoplasma gondii

Abstract

The immune system operates the protection against infections by selecting efficient pathways depending on the pathogen. Toxoplasma gondii, an obligate intracellular protozoan parasite, has two lifecycle stages, tachyzoite and cyst, in intermediate hosts including humans. Tachyzoite is the acute stage form that quickly proliferates within host cells. Cyst is the chronic stage form that can slowly grow into more than 100 mm in diameter by containing hundreds to thousands of bradyzoites. Our studies on the IFN-g-mediated protective immunity against cerebral tachyzoite growth revealed that IFN-g production by brain-resident cells is not only required for upregulation of the innate protective immunity to limit cerebral tachyzoite proliferation during the early stage of the tachyzoite growth but also crucial for recruiting immune T cells from the periphery and activation of the recruited T cells to ultimately prevent the tachyzoite growth. Since IFN-g is crucial for the protective immunity against various intracellular microorganisms in the brain, it is possible that IFN-gproduced by brain-resident cells plays a key first line defense role by orchestrating both the innate and T cell-mediated protective immunity to control not only T. gondii but also the other intracellular pathogens. Our studies on the protective immunity against T. gondii cysts uncovered the capability of cytotoxic T cells to penetrate into the target in a perforin-dependent manner for its elimination. After penetrating into the target, the cytotoxic T cells secrete granzyme B, which associates with an accumulation of phagocytes to eliminate the parasite. Since the presence of tumor-infiltrating CD8⁺ T cells in solid cancers is an indicator of positive prognosis of cancer patients, the perforin-mediated penetration of CD8⁺ T cells and an accumulation of phagocytes could function as a powerful protective mechanism against not only T. gondiicysts but also targets of large mass in general such as solid cancers.