DOWN-REGULATION OF MHC CLASS-II MOLECULES AND INABILITY TO UP-REGULATE CLASS-I MOLECULES IN MURINE MACROPHAGES AFTER INFECTION WITH TOXOPLASMA-GONDII

Toxoplasma gondii is able to invade phagocytic cells of the monocyte-m acrophage lineage and replicates within a parasitophorous vacuole. Sin ce macrophages may activate specific T lymphocytes by presenting patho gen-derived antigens in association with molecules of the MHC, we inve stigated the in vitro expression of host cell molecules involved in an tigen processing and presentation before and during infection of murin e bone marrow-derived macrophages (BMM) with T. gondii. Fifty-one hour s after addition of T. gondii tachyzoites at different parasite-to-hos t ratios, up-regulation of total MHC class II molecules by interferon- gamma (IFN-gamma) was dose-dependently abrogated in up to 50% of macro phages compared with uninfected control cultures. Quantitative analyse s by flow cytometry revealed that the IFN-gamma-induced surface expres sion of class II antigens as well as the IFN-gamma-induced upregulatio n of class I molecules was significantly decreased in T. gondii-infect ed macrophage cultures compared with uninfected controls. However, the constitutive expression of MHC class I antigens was not altered after parasitic infection, and infected BMM remained clearly positive for t hese molecules. After infection of macrophages preactivated with IFN-g amma for 48 h, T. gondii also actively down-regulated an already estab lished expression of MHC class II molecules. Furthermore, kinetic anal ysis revealed that the reduction in intracellular and plasma membrane- bound class II molecules started approximate to 20h after infection. W hile MHC class II antigens were most prominently reduced in parasite-p ositive host cells, culture supernatant from T. gondii-infected BMM cu ltures also significantly inhibited expression of these molecules in u ninfected macrophages. However, down-regulation of MHC class II molecu les was not mediated by an increased production of prostaglandin E-2, IL-IO, transforming growth factor-beta or nitric oxide by infected BMM compared with uninfected controls. Our data indicate that intracellul ar T. gondii interferes with the MHC class I and class LI antigen pres entation pathway of murine macrophages and this may be an important st rategy for evasion from the host's immune response and for intracellul ar survival of the parasite.